Acetamide derivative, process for preparing the same, and a pharmaceutical composition containing the same

ABSTRACT

An acetamide derivative of the formula (I): ##STR1## wherein X is --0-- or --NR 4  --, R 1  is H, lower alkyl, lower alkenyl or cyclolalkyl-lower-alkyl, R 2  is lower alkyl, cycloalkyl, substituted or unsubstituted phenyl, etc., R 3  is H, lower alkyl or hydroxy-lower alkyl, R 4  is H, lower alkyl, etc., R 5  is H, lower alkyl, lower alkenyl, hydroxy-lower alkyl, etc., R 6  is H, lower alkyl, CF 3 , substituted or unsubstituted phenyl, or R 5  and R 6  may optionally combine to form --(CH 2 )n--, R 7  is H, halogen, lower alkyl, lower alkoxy, CF 3 , OH, NH 2 , etc., R 8  is H, halogen, lower alkyl or lower alkoxy, or a pharmaceutically acceptable acid addition salt thereof. The compounds of the present invention selectively act on the peripheral-type BZω 3  -receptor, and show excellent pharmacological activities, and hence, they are useful in the prophylaxis or treatment of central nervous disorders such as anxiety-related diseases, depression, epilepsy, etc.

TECHNICAL FIELD

The present invention relates to a novel acetamide derivativeselectively acting on the peripheral-type benzodiazepine receptors, moreparticularly, an acetamide derivative having 2-phenyl-4-pyrimidinylaminomoiety or 2-phenyl-4-pyrimidinyloxy moiety, a process for preparing thesame, and a pharmaceutical composition containing the same.

BACKGROUND ART

In the central nervous system of the mammals, including human, there arethree kinds of benzodiazepine (hereinafter, occasionally referred to asBZ) recognition sites, and each is named as central-type (ω₁, ω₂)benzodiazepine receptors and a peripheral-type (ω₃) benzodiazepinereceptor, respectively (hereinafter, occasionally referred to as BZω₁-receptor, BZω₂ -receptor and BZω₃ -receptor, respectively). Among them,the peripheral-type BZ-receptor unevenly distributes in the peripheraltissues or organs such as kidney, liver, heart, etc., but it especiallydistributes with high density in the cells of the endocrinium organssuch as adrenal glands, testicles, etc., or in the cells deeplyparticipating in the inflammation-immune system in whole body such asmast cells, lymphocytes, macrophages, blood platelets, etc., so that thephysiological roles of the peripheral-type BZ-receptor have recentlybeen drawing attention.

On the other hand, the peripheral-type BZ-receptor is present a lot inthe mitochondrial membrane of glial cells in the brain, and itparticipates in cholesterol influx into the mitochondrial membrane, andhence, it is thought to act on the biosynthesis pathway of cholesterolinto neurosteroids such as allopregnanolone,allotetrahydrodeoxycorticosterone (THDOC), etc. via pregnenolone. Thus,it is considered that stimulation of the peripheral-type BZ-receptoraccelerates the synthesis of neurosteroids in the brain which affect thechoride ion channel gating process by binding to theneurosteroid-specific recognition site on the γ-aminobutyricacid-A-receptor (hereinafter, occasionally referred to as GABA_(A)-receptor) [cf. Romeo, E., et al., J. Pharmacol. Exp. Ther., 262,971-978 (1992)].

A compound having a non-BZ nucleus and selectively showing an affinityfor the peripheral-type BZ-receptor has been disclosed in JapanesePatent First Publication (Kokai) No. 201756/1983 (EP-A-94271), and sincethen, various compounds are disclosed in many literatures includingpatent applications. However, there is no compound which has actuallybeen used as a medicament.

As a compound having a non-BZ nucleus and selectively showing anaffinity for the peripheral-type BZ-receptors, in addition to the above,there have been known the compounds disclosed in Japanese Patent FirstPublication (Kokai) Nos. 5946/1987 and 32058/1990.

Japanese Patent First Publication (Kokai) No. 5946/1987 (EP-A-205375,U.S. Pat. No. 4,788,199) discloses amide compounds of the followingformula, which are bound to the peripheral-type BZ-receptor, and areuseful as anxiolytics, anticonvulsants and antiangina agents, and forthe treatment of immuno-deficiency syndrome. ##STR2## wherein A is anitrogen atom or ═CH--; B is a nitrogen atom or ═CH--; V and W are thesame or different and each a hydrogen atom, a halogen atom, an alkylgroup or an alkoxy group both having 1 to 3 carbon atom, etc.; Z isbound in the ortho- or para-position with respect to the B, and is aphenyl group, a thienyl group, a pyridyl group, or a phenyl groupsubstituted by 1 to 2 groups selected from a halogen atom, an alkylgroup or an alkoxy group both having 1 to 4 carbon atoms,trifluoromethyl group and a nitro group; a chain of --X--(CH₂)_(n)--(CHR)_(m) --CONR₁ R₂ is bound in the ortho- or para-position withrespect to the B; R is a hydrogen atom or an alkyl group having 1 to 3carbon atoms; R₁ and R₂ are the same or different and each a straightchain or branched chain alkyl group having 1 to 6 carbon atoms, acycloalkyl group having 3 to 6 carbon atoms, a phenyl group, aphenylalkyl group or a cyclo-alkylalkyl group wherein the alkyl moietyhas 1 to 3 carbon atoms and the cycloalkyl moiety has 3 to 6 carbonatoms, or an alkenyl group having 3 to 6 carbon atoms wherein the doublebond is not located at the 1,2-position with respect to the nitrogenatom, and R₁ and R₂ may combine together with the nitrogen atom to whichthey are attached to form pyrrolidine, piperidine, morpholine orthiomorpholine ring; X is --CHR₃ --, --NR₄ --, --SO--, --SO₂ --, anoxygen atom or a sulfur atom; R₃ is a hydrogen atom or an alkyl grouphaving 1 to 3 carbon atoms; R₄ is an alkyl group having 1 to 3 carbonatoms; m is 0 or 1; and is 0, 1 or2,

provided that when X is --SO--, --SO₂ -- or --NR₄ --, the total numberof m+n should be at least 1, and that when both of A and B are anitrogen atom and Z is at the para-position with respect to the B, Xshould not be --CHR₃ --, and that when A is ═CH--, B is a nitrogen atom,Z is in the ortho-position with respect to the B, X is an oxygen atomand R is a hydrogen atom, the total number of m+n is other than 1, andexcluding 2-phenyl-4-quinolyl-N,N-dimethylcarbamate.

Japanese Patent First Publication (Kokai) No. 32058/1990 (EP-A-346208,U.S. Pat. No. 5026711) discloses that 4-amino-3-carboxyquinolinecompounds of the following formula show an affinity for theperipheral-type BZ-receptor both in vivo and in vitro, and can be usedin the prophylaxis or treatment of human cardiovascular diseases, or asan antiallergic agent, or in the prophylaxis or treatment of infectiousdiseases, or in the treatment of anxiety. ##STR3## wherein R₁ and R₂ areeach a hydrogen atom, a C₁ -C₆ alkyl group, or a C₂ -C₆ alkenyl group, aphenyl group or a benzyl group, or R₁ and R₂ may combine together withthe nitrogen atom to which they are attached to form a C₄ -C₈ saturatedheterocyclic group; R₃ is a hydrogen atom, a C₁ -C₆ alkyl group, aphenyl group or a C₇ -C₉ phenylalkyl group; R₄ is a hydrogen atom or aC₁ -C₄ alkyl group; R₅ and R₆ are each a hydrogen atom, a halogen atom,a C₁ -C₃ alkyl or alkoxy group, a nitro group, or a trifluoromethylgroup, or combine together to form a methylenedioxy group; Z is OR₇ (R₇is a hydrogen atom or a C₁ -C₆ alkyl group), NR₈ R₉ (R₈ and R₉ are eacha hydrogen atom, a C₁ -C₄ alkyl group, a phenyl group or a benzylgroup), a C₁ -C₄ alkyl group, a benzyl group, a C₄ -C₆ aryl group whichmay optionally have a heteroatom; R₁₀ is a hydrogen atom, a C₁ -C₄ alkylgroup or a phenyl group (provided that when Z is not a benzyl group oran aryl group, R₃ is not a hydrogen atom, and a phenyl group and abenzyl group may optionally be substituted by a halogen atom, a C₁ -C₃alkoxy, alkyl or thioalkyl group, a nitro group, a trifluoromethyl groupor a hydroxy group, and these alkyl and alkoxy groups are straightchain, branched chain or cyclic ones, respectively); n is 0, 1 or 2; pis 0 or 1; one of A, B, C and D is N, and the other ones are each CH, orall A, B, C and D are each CH.

On the other hand, there are known some acetamide derivatives having a2-phenyl-4-pyrimidinylamino moiety. For example, U.S. Pat. No. 3,631,036discloses some compounds represented by2-(5-cyano-2-phenyl-4-pyrimidinyl-amino) acetamide as a syntheticintermediate for5-amino-2,6-di-substituted-7H-pyrrolo[2,3-d]pyrimidines. U.S. Pat. No.3,631,045 discloses some compounds represented by2-(5-cyano-6-methylamino-2-phenyl-4-pyrimidinylamino)-acetamide as asynthetic intermediate for 4,5-diamino-7H-pyrrolo[2,3-d]-pyrimidines.However, the pharmacological activities of these compounds have neverbeen disclosed yet.

Besides, Pharmazie, 43, 537-538 (1988) discloses some compoundsrepresented by2-(5-acetyl-6-methyl-2-phenyl-4-pyrimidinylthio)-N-(4-chloro-phenyl)acetamide and2-(5-acetyl-6-methyl-2-phenyl-4-pyrimidinylthio)-N-(4-methylphenyl)acetamide, as a synthetic intermediate for thieno[2,3-d]pyrimidinederivatives. Moreover, it is also disclosed in said literature that2-(5-acetyl-6-methyl-2-phenyl-4-pyrimidinylthio)-N-(4-chlorophenyl)acetamideshows antibacterial activity against Bacillus subtilis.

DISCLOSURE OF INVENTION

The present inventors have intensively studied in order to prepare acompound acting selectively and potently on BZω₃ -receptor, and havefound the acetamide derivatives of the following formula (I), andfinally have accomplished the present invention.

An object of the present invention is to provide a novel acetamidederivative acting selectively and potently on BZω₃ -receptor, moreparticularly, to provide an acetamide derivative having a2-phenyl-4-pyrimidinylamino moiety or a 2-phenyl-4-pyrimidinyloxymoiety. Especially, the present invention provides a useful compoundhaving an anxiolytic activity and being useful in the treatment ofimmune diseases. Another object of the present invention is to provide aprocess for preparing said compound. Still further object of the presentinvention is to provide a pharmaceutical composition containing saidcompound. These objects and the advantageous features of the presentinvention are obvious to any skilled person in this art from thefollowing description.

The present invention provides an acetamide derivative of the followingformula (I), a pharmaceutically acceptable acid addition salt thereof(hereinafter, occasionally referred to as "the compound of the presentinvention"), a process for preparing the same, and a pharmaceuticalcomposition containing the same. ##STR4## wherein X is --O-- or --NR₄--, R₁ is a hydrogen atom, a lower alkyl group, a lower alkenyl group ora cyclolalkyl-lower alkyl group,

R₂ is a lower alkyl group, a cycloalkyl group, a substituted orunsubstituted phenyl group, or a substituted or unsubstitutedphenyl-lower alkyl group, or R₁ and R₂ may optionally combine togetherwith the nitrogen atom to which they are attached to form a group of theformula: ##STR5## wherein A is a single bond, --CH₂ --, --O-- or --NH--,R_(a) and R_(b) are the same or different and each a hydrogen atom or alower alkyl group, or when A is a single bond, and R_(a) and R_(b) arelocated at the 2-position and the 3-position, respectively, the carbonatoms of the 2-position and the 3-position and R_(a) and R_(b) mayoptionally combine to form a phenyl ring, R₃ is a hydrogen atom, a loweralkyl group or a hydroxy-lower alkyl group,

R₄ is a hydrogen atom or a lower alkyl group, or R₃ and R₄ mayoptionally combine together with the carbon atom and the nitrogen atomto which they are attached to form pyrrolidine, piperidine, or2,3-dihydro-1H-indole ring,

R₅ is a hydrogen atom, a lower alkyl group, a lower alkenyl group, ahydroxy-lower alkyl group, a substituted or unsubstitutedbenzyloxy-lower alkyl group, an acyloxy-lower alkyl group, a loweralkoxy-lower alkyl group, a trifluoromethyl group, a halogen atom, anamino group, a mono- or di-lower alkylamino group, an acylamino group,an amino-lower alkyl group, a nitro group, a carbamoyl group, a mono- ordi-lower alkylcarbamoyl group, a carboxyl group, a protected carboxylgroup, a carboxy-lower alkyl group or a protected carboxy-lower alkylgroup,

R₆ is a hydrogen atom, a lower alkyl group, a trifluoromethyl group or asubstituted or unsubstituted phenyl group, or R₅ and R₆ may optionallycombine to form --(CH₂)_(n) --(n is 3, 4, 5 or 6),

R₇ is a hydrogen atom, a halogen atom, a lower alkyl group, a loweralkoxy group, a trifluoromethyl group, a hydroxy group, an amino group,a mono- or di-lower alkylamino group, a cyano group or a nitro group,

R₈ is a hydrogen atom, a halogen atom, a lower alkyl group or a loweralkoxy group.

The pharmaceutically acceptable acid addition salt of the compound ofthe formula (I) includes a pharmaceutically acceptable acid additionsalt of the compound of the formula (I) which shows basicity enough toform an acid addition salt thereof, for example, a salt with aninorganic acid such as hydrochloride, hydrobromide, hydroiodide,sulfate, phosphate, etc., or a salt with an organic acid such asmaleate, fumarate, oxalate, citrate, tartrate, lactate, benzoate,methanesulfonate, etc. The compound of the formula (I) and an acidaddition salt thereof may exist in the form of a hydrate and/or asolvate, and the present invention also includes these hydrates andsolvates as well.

The compound of the formula (I) may have one or more asymmetric carbonatoms, and by which stereoisomers thereof are possible, and the compoundof the formula (I) may exist in a mixture of two or more stereoisomers.The present invention also includes these stereoisomers, a mixturethereof, and a racemic mixture thereof.

The terms used in the present description and claims are explainedbelow.

The lower alkyl group and the lower alkoxy group include a straightchain or branched chain alkyl or alkoxy group having 1 to 6 carbonatoms, respectively, unless defined otherwise. The lower alkyl group is,for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl,and hexyl. The lower alkyl groups for R₃, R₄, R₅, R₆, R₇ and R₈ arepreferably ones having 1 to 4 carbon atoms. The lower alkoxy group is,for example, methoxy, ethoxy, propoxy, and butoxy. The lower alkenylgroup includes ones having a double bond except for between the 1- and2-positions, and having 3 to 6 carbon atoms, for example, allyl, and2-butenyl. The cycloalkyl group includes ones having 3 to 8 carbonatoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. The cycloalkyl-lower alkyl group includesan alkyl group having 1 to 4 carbon atoms which is substituted by one ofthe above mentioned cycloalkyl groups, for example, cyclopropylmethyl,cyclopentylmethyl, and cyclohexylmethyl. The halogen atom is fluorine,chlorine, bromine, and iodine.

The substituted or unsubstituted phenyl group includes a phenyl groupwhich may optionally be substituted by one or two groups selected from ahalogen atom, a C₁ -C₃ alkyl group, a C₁ -C₃ alkoxy group, atrifluoromethyl group, an amino group, a mono- or di-C₁ -C₃ alkylaminogroup, a cyano group and a nitro group, for example, phenyl; 2-, 3- or4-chlorophenyl; 2-, 3- or 4-bromophenyl; 2-, 3- or 4-fluorophenyl;2,4-dichlorophenyl; 2,4-dibromophenyl; 2,4-difluorophenyl; 2-, 3- or4-methylphenyl, 2-, 3- or 4-methoxyphenyl, 2-, 3- or4-trifluoromethylphenyl; 2-, 3- or 4-aminophenyl; 2-, 3- or4-methylaminophenyl; 2-, 3- or 4-dimethylaminophenyl; 2-, 3- or4-cyanophenyl; and 2-, 3- or 4-nitrophenyl.

The examples of a group of the formula: ##STR6## includes ones beingexemplified above for the substituted or unsubstituted phenyl group, andmore preferable ones are phenyl, 4- or 3-chlorophenyl, 4- or3-bromophenyl, 4-or 3-fluorophenyl, and 4-methoxyphenyl. The substitutedor unsubstituted phenyl-lower alkyl group includes an alkyl group having1 to 4 carbon atoms which is substituted by one of the above mentionedsubstituted or unsubstituted phenyl groups, for example, benzyl, 2-, 3-or 4-chlorobenzyl, 4-bromobenzyl, 3- or 4-fluorobenzyl, 4-methylbenzyl,4-methoxybenzyl, phenethyl, and 2-(4-chlorophenyl)ethyl.

The hydroxy-lower alkyl group includes an alkyl group having 1 to 4carbon atoms which is substituted by a hydroxy group, for example,hydroxy-methyl, 2-hydroxyethyl, and 3-hydroxypropyl. The substituted orunsubstituted benzyloxy-lower alkyl group includes a lower alkyl groupsubstituted by one or two groups selected from a benzyloxy group whereinthe phenyl moiety may optionally be substituted by a halogen atom, a C₁-C₃ alkyl group and a C₁ -C₃ alkoxy group, for example, benzyloxymethyl,2-, 3- or 4-chlorobenzyloxymethyl, 3-bromobenzyloxymethyl,4-fluorobenzyloxymethyl, 2,4- or 3,4-dichlorobenzyloxymethyl,4-methylbenzyloxymethyl, 2-, 3- or 4-methoxybenzyloxymethyl, and2-benzyloxyethyl. The acyl group includes an alkanoyl group having 2 to4 carbon atom or a benzoyl group which may optionally be substituted bya halogen atom, a C₁ -C₃ alkyl group or a C₁ -C₃ alkoxy group, forexample, acetyl, propionyl, benzoyl, 2-, 3- or 4-chlorobenzoyl, 2-, 3-or 4-bromobenzoyl, 2-, 3- or 4-fluorobenzoyl, 4-methylbenzoyl, and4-methoxybenzoyl. The acyloxy-lower alkyl group includes a lower alkylgroup substituted by an acyloxy group which is introduced from the abovementioned acyl groups, for example, acetoxymethyl, benzoyloxymethyl,4-chlorobenzoyl-oxymethyl, 3-bromobenzoyloxymethyl,4-fluorobenzoyloxymethyl, 2-methyl-benzoyloxymethyl, and4-methoxybenzoyloxymethyl. The lower alkoxy-lower alkyl group includesan alkyl group having 1 to 4 carbon atoms which is substituted by analkoxy group having 1 to 4 carbon atoms, for example, methoxymethyl,ethoxymethyl, 2-methoxyethyl, and 3-methoxypropyl.

The mono- or di-lower alkylamino group includes an amino groupsubstituted by one or two alkyl groups having 1 to 4 carbon atoms, forexample, methylamino, ethylamino, propylamino, dimethylamino,diethylamino, dipropyl-amino, and ethylmethylamino. The acylamino groupincludes an amino group substituted by the above mentioned acyl group,for example, acetylamino, propionylamino, benzoylamino,4-chlorobenzoylamino, and 4-fluorobenzoylamino. The amino-lower alkylgroup includes an alkyl group having 1 to 4 carbon atoms which issubstituted by an amino group, for example, aminomethyl, 2-aminoethyl,and ³ -aminopropyl. The mono- or di-lower alkyl-carbamoyl group includesa carbamoyl group substituted by one or two alkyl groups having 1 to 4carbon atoms, for example, methylcarbamoyl, dimethylcarbamoyl,diethylcarbamoyl, and dipropylcarbamoyl. The protected carboxyl groupincludes a carboxyl group which is protected by a protecting group whichcan easily be removed by hydrolysis or hydrogenolysis, for example, acarboxyl group protected by a C₁ -C₄ alkyl group or by a benzyl groupwhich may optionally be substituted by one or two groups selected from ahalogen atom, a C₁ -C₃ alkyl group and a C₁ -C₃ alkoxy group. Theexamples of the protected carboxyl group are methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, benzyloxycarbonyl,4-chlorobenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl,4-methylbenzyloxycarbonyl, and 4-methoxybenzyloxycarbonyl. Among them,methoxycarbonyl, ethoxycarbonyl and benzyloxycarbonyl are preferable.The protected carboxy-lower alkyl group includes an alkyl group having 1to 4 carbon atoms which is substituted by the above mentioned protectedcarboxyl group, for example, methoxy-carbonylmethyl,ethoxycarbonylmethyl, benzyloxycarbonylmethyl, and2-ethoxycarbonylethyl.

Among the compounds of the present invention, the preferable one is acompound of the formula (I) wherein R₁ and R₂ are the same or differentand each a lower alkyl group, or R₁ is a lower alkyl group, a loweralkenyl group or a cycloalkyl-lower alkyl group, R₂ is a substituted orunsubstituted phenyl group, or R₁ and R₂ may combine together with thenitrogen atom to which they are attached to form a group of the formula:##STR7## (wherein A' is --CH₂ -- or --O--, R_(a) ' and R_(b) ' are thesame or different and each a lower alkyl group), R₅ is a hydrogen atom,a lower alkyl group, a hydroxy-lower alkyl group, a halogen atom, anamino group, an acylamino group, a nitro group or a protected carboxylgroup, and X, R₃, R₆, R₇ and R₈ are the same as defined above, or apharmaceutically acceptable acid addition salt thereof.

The more preferable compound of the present invention is a compound ofthe formula (I) wherein R₁ and R₂ are the same or different and eachmethyl group, ethyl group, propyl group, isopropyl group or butyl group,or R₁ is methyl group, ethyl group, propyl group, isopropyl group, butylgroup, allyl group or cyclopropylmethyl group, R₂ is phenyl group, or aphenyl group substituted by a halogen atom or methoxy group, R₃ is ahydrogen atom, R₅ is a hydrogen atom, methyl group, ethyl group orhydroxymethyl group, R₆ is methyl group or phenyl group, or R₅ and R₆may optionally combine to form --(CH₂)₄ --, R₇ is a hydrogen atom, ahalogen atom, a C₁ -C₃ alkoxy group, trifluoromethyl group, amino groupor nitro group, R₈ is a hydrogen atom, and X and R₄ are the same asdefined above, or a pharmaceutically acceptable acid addition saltthereof.

The further preferable compound of the present invention is a compoundof the formula (I) wherein X is --O-- or --NR₄ '--, R₁ and R₂ are thesame or different and each ethyl group, propyl group or butyl group, orR₁ is methyl group, ethyl group, propyl group, allyl group orcyclopropylmethyl group, and R₂ is phenyl group, a halogenophenyl groupor a methoxyphenyl group, R₃ is a hydrogen atom, R₄ ' is a hydrogenatom, methyl group or ethyl group, or R₃ and R₄ ' may optionally combinetogether with the carbon atom and the nitrogen atom to which they areattached to form pyrrolidine ring or 2,3-dihydro-1H-indole ring, R₇ is ahydrogen atom, a halogen atom, methoxy group, trifluoro-methyl group,amino group or nitro group, R₈ is a hydrogen atom, R₅ and R₆ are thesame as defined just in the above, or a pharmaceutically acceptable acidaddition salt thereof.

The especially preferable compound of the present invention is anacetamide derivative of the following formula (I') or the formula (I"),or a pharmaceutically acceptable acid addition salt thereof. ##STR8##wherein X' is --O-- or --NR₄ "--, R₁ ' and R₂ ' are both ethyl group orpropyl group, or R₁ ' is methyl group, ethyl group, propyl group, allylgroup or cyclopropylmethyl group, and R₂ ' is phenyl group,4-halogenophenyl group, or 4-methoxyphenyl group, R₃ ' is a hydrogenatom, R⁴ " is a hydrogen atom, methyl group or ethyl group, R₇ ' is ahydrogen atom, a halogen atom, methoxy group, a trifluoromethyl group,an amino group or a nitro group. Further, among the compounds of theformula (I'), the compounds of the formula (I') wherein X' is --O-- orX' is --NH-- are most preferable. ##STR9## wherein R₅ ' is a hydrogenatom, methyl group or ethyl group, and R₁ ', R₂ ' and R₇ ' are the sameas defined above.

The examples of the most preferable compound of the present inventionare the following compounds and pharmaceutically acceptable acidaddition salts thereof.

2-[2-(4-Chlorophenyl)-5,6-dimethyl-4-pyrimidinylamino]-N,N-dipropylacetamide;

2-[2-(4-Chlorophenyl)-5,6-dimethyl-4-pyrimidinylamino]-N,N-diethylacetamide;

2-[2-(4-Chlorophenyl)-5,6-dimethyl-4-pyrimidinylamino]-N-methyl-N-phenylacetamide;

N-(4-Chlorophenyl)-N-methyl-2-(5,6-dimethyl-2-phenyl-4-pyrimidinylamino)acetamide;

2-[2-(4-Chlorophenyl)-5,6-dimethyl-4-pyrimidinylamino]-N-(4-fluorophenyl)-N-methylacetamide;

2-[2-(4-Chlorophenyl)-5,6-dimethyl-4-pyrimidinylamino]-N-(4-methoxyphenyl)-N-methylacetamide;

2-(5,6-Dimethyl-2-phenyl-4-pyrimidinylamino)-N-phenyl-N-propylacetamide;

2-[2-(4-Chlorophenyl)-5,6-dimethyl-4-pyrimidinylamino]-N-ethyl-N-phenylacetamide;

2-(5,6-Dimethyl-2-phenyl-4-pyrimidinyloxy)-N,N-dipropylacetamide;

2-(2,6-Diphenyl-4-pyrimidinylamino)-N,N-dipropylacetamide;

2-[5,6-Dimethyl-2-(4-trifluoromethylphenyl)-4-pyrimidinylamino]-N,N-dipropylacetamide;

2-[2-(4-Aminophenyl)-5,6-dimethyl-4-pyrimidinyloxy]-N-ethyl-N-phenyl-acetamide;

N-(4-Chlorophenyl)-N-methyl-2-(5,6-dimethyl-2-phenyl-4-pyrimidinyloxy)acetamide;and

2-(5,6-Dimethyl-2-phenyl-4-pyrimidinyloxy)-N-phenyl-N-propylacetamide

The representative compounds of the present invention are, in additionto the compounds of the following Examples, the compounds of thefollowing Tables 1 to 4, and a pharmaceutically acceptable acid additionsalt thereof.

In Tables 1 to 4, the following Reference Examples and Examples, thefollowing abbreviations are used in order to simplify the disclosure.

Ac: Acetyl group

Me: Methyl group

Et: Ethyl group

Pr: Propyl group

i-Pr: Isopropyl group

Bu: Butyl group

i-Bu: Isobutyl group ##STR10## Ph: Phenyl group

Thus, for example, Ph-4-Cl means 4-chlorophenyl group, and Ph-4-F means4-fluorophenyl group.

                  TABLE 1                                                         ______________________________________                                        1 #STR11##                                                                    R.sub.1 R.sub.2         R.sub.7 X                                             ______________________________________                                        Me      Ph-2-F          H       NH                                            Me      Ph-2-Br         H       NH                                            i-Pr    i-Pr            4-Cl    NH                                            Me      Ph-2-Cl         4-Cl    NH                                            Me      Ph-3-F          4-Cl    NH                                            Et      Ph-4-Cl         4-Cl    NH                                            Et      Ph-4-F          4-Cl    NH                                            Pr      Pr              2-Br    NH                                            Pr      Pr              4-Br    NH                                            Bu      Bu              4-Br    NH                                            Me      Ph              4-Br    NH                                            Me      Ph              4-Br    NH                                            Et      Ph-4-Cl         4-Br    NH                                            Pr      Pr              3-F     NH                                            Me      Ph              2-F     NH                                            Me      Ph-2-Cl         4-F     NH                                            Me      Ph-3-Cl         4-F     NH                                            Me      Ph-2-F          4-F     NH                                            Et      Ph-4-F          4-F     NH                                            Bu      Bu              4-OMe   NH                                            Me      Ph-3-F          4-OMe   NH                                            Et      Ph-4-F          4-OMe   NH                                            Pr      Pr              4-OH    NH                                            Me      Ph              4-NH.sub.2                                                                            NH                                            Bu      Bu              H       NMe                                           Me      Ph-4-Cl         4-F     NMe                                           Me      Ph-4-F          4-Cl    NMe                                           Pr      Pr              H       NEt                                           Pr      Pr              4-F     NEt                                           Me      Ph              4-Cl    NPr                                           Pr      Pr              4-NH.sub.2                                                                            O                                             i-Pr    i-Pr            4-Cl    O                                             Bu      Bu              4-Cl    O                                             Me      Ph              4-NH.sub.2                                                                            O                                             Me      Ph-4-Cl         3-F     O                                             Me      Ph-2-F          4-Cl    O                                             Et      Ph-4-Cl         H       O                                             Et      Ph-4-Cl         4-F     O                                             Et      Ph-4-F          4-Cl    O                                             ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        2 #STR12##                                                                    R.sub.1                                                                              R.sub.2    R.sub.5                                                                              R.sub.9  R.sub.7                                                                            X                                      ______________________________________                                        Et     Et         H      H        4-Cl NH                                     Pr     Pr         H      H        4-F  NH                                     Pr     Pr         H      H        2-F  NH                                     i-Pr   i-Pr       H      H        H    NH                                     Bu     Bu         H      H        H    NH                                     Bu     Bu         H      H        4-F  NH                                     Me     Ph         H      H        4-F  NH                                     Me     Ph         H      H        3-Cl NH                                     Me     Ph-4-Cl    H      H        4-Cl NH                                     Me     Ph-2-Cl    H      H        4-F  NH                                     Me     Ph-4-F     H      H        4-Cl NH                                     Me     Ph-2-F     H      H        4-F  NH                                     Et     Ph         H      H        4-Cl NH                                     Et     Ph-4-Cl    H      H        H    NH                                     Pr     Pr         Me     H        4-F  NH                                     i-Pr   i-Pr       Me     H        4-Cl NH                                     Bu     Bu         Me     H        4-F  NH                                     Me     Ph         Me     H        4-Cl NH                                     Me     Ph-4-Cl    Me     H        H    NH                                     Me     Ph-4-Cl    Me     H        4-F  NH                                     Me     Ph-4-F     Me     H        4-Cl NH                                     Et     Ph         Me     H        H    NH                                     Et     Ph         Me     H        4-Cl NH                                     Pr     Pr         H      4-Cl     4-F  NH                                     Bu     Bu         H      4-NO.sub.2                                                                             4-F  NH                                     Me     Ph-4-Cl    H      2-Me     H    NH                                     Pr     Pr         Me     4-Cl     4-F  NH                                     Bu     Bu         Me     4-NO.sub.2                                                                             4-F  NH                                     Me     Ph-4-Cl    Me     2-Me     H    NH                                     Et     Et         H      H        3-Cl O                                      Pr     Pr         H      H        4-Cl O                                      i-Pr   i-Pr       H      H        4-F  O                                      Bu     Bu         H      H        4-Cl O                                      Me     Ph         H      H        4-Cl O                                      Me     Ph-4-Cl    H      H        4-F  O                                      Et     Ph         H      H        2-Cl O                                      Et     Ph-4-Cl    H      H        H    O                                      Et     Et         Me     H        4-Cl O                                      Pr     Pr         Me     H        H    O                                      Pr     Pr         Me     H        4-Cl O                                      i-Pr   i-Pr       Me     H        3-F  O                                      Bu     Bu         Me     H        2-Cl O                                      Me     Ph-4-Cl    Me     H        4-F  O                                      Et     Ph         Me     H        4-Cl O                                      Et     Ph-4-Cl    Me     H        H    O                                      Pr     Pr         H      4-Cl     H    O                                      Me     Ph-4-Cl    H      4-NO.sub.2                                                                             4-F  O                                      Pr     Pr         Me     4-F      4-Cl O                                      Me     Ph         Me     4-OMe    4-F  O                                      ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                        3 #STR13##                                                                    R.sub.1   R.sub.2 n          R.sub.7                                                                            X                                           ______________________________________                                        Pr        Pr      3          4-Cl NH                                          Pr        Pr      5          2-F  NH                                          Pr        Pr      3          4-F  O                                           Pr        Pr      5          H    O                                           Me        Ph      3          H    NH                                          Me        Ph      5          4-F  NH                                          Me        Ph-4-Cl 6          4-Cl NH                                          Me        Ph-4-Cl 3          4-F  O                                           Me        Ph-4-F  5          H    O                                           Me        Ph-4-F  6          4-Cl O                                           ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                        4 #STR14##                                                                    R.sub.1                                                                              R.sub.2     R.sub.5      R.sub.6                                       ______________________________________                                        Me     Ph          --CH.sub.2 CH.sub.2 OH                                                                     H                                             Pr     Pr          --CH.sub.2 OCH.sub.2 Ph                                                                    H                                             Pr     Pr          --CH.sub.2 OAc                                                                             H                                             Pr     Pr          --CH.sub.2 OCOPh                                                                           H                                             Me     Ph          --CH.sub.2 OMe                                                                             H                                             Me     Ph          --NHMe       H                                             Me     Ph          --NEt.sub.2  H                                             Me     Ph          --CH.sub.2 NH.sub.2                                                                        H                                             Me     Ph          --CONH.sub.2 H                                             Pr     Pr          --CONHMe     H                                             Pr     Pr          --CONEt.sub.2                                                                              H                                             Me     Ph          --COOH       H                                             Me     Ph          --COOEt      H                                             Me     Ph          --COOCH.sub.2 Ph                                                                           H                                             Pr     Pr          --CH.sub.2 COOH                                                                            H                                             Pr     Pr          --CH.sub.2 COOEt                                                                           H                                             Pr     Pr          Pr           Me                                            Pr     Pr          --CH.sub.2 OH                                                                              Me                                            Pr     Pr          --CH.sub.2 CH═CH.sub.2                                                                 Me                                            Me     Ph          Me           Et                                            Me     Ph          Et           Et                                            Me     Ph          Pr           Pr                                            Me     Ph          Me           CF.sub.3                                      ______________________________________                                    

The compounds of the present invention may be prepared, for example, bythe following processes.

Process (a)

The compound of the formula (I) wherein X is --NR₄ -- is prepared byreacting a compound of the formula (II): ##STR15## wherein Z is aleaving atom or a leaving group, R₅₁ is the same groups as defined abovefor R₅ except that a hydroxy-lower alkyl group, an amino group, anamino-lower alkyl group, a carboxyl group and a carboxy-lower alkylgroup are protected ones, and R₆, R₇ and R₈ are the same as definedabove, with a compound of the formula (III): ##STR16## wherein R₃₁ is ahydrogen atom, a lower alkyl group or a protected hydroxy-lower alkylgroup, and R₁, R₂ and R₄ are the same as defined above, if necessary,followed by removing the protecting groups from the product.

The leaving atom or the leaving group represented by Z in the aboveformula (II) includes an atom or a group which may be removed in theform of HZ together with the hydrogen atom of the NH moiety of thecompound (III) under the reaction conditions, for example, a halogenatom (e.g. chlorine, bromine, iodine), a lower alkylsulfonyloxy group(e.g. methanesulfonyloxy), a trihalogenomethanesulfonyloxy group (e.g.trifluoromethanesulfonyloxy), and an arylsulfonyloxy group (e.g.benzenesulfonyloxy, p-toluenesulfonyloxy).

The protected hydroxy group for R₃₁ or R₅₁ in the above formulae (II)and (III) includes a hydroxy group being protected by a protecting groupwhich may be removed by hydrogenolysis, for example, benzyloxy,4-chlorobenzyloxy, 3-bromobenzyloxy, 4-fluorobenzyloxy,4-methylbenzyloxy, and 4-methoxybenzyloxy. The protected amino group orprotected amino moiety for R₅₁ in the formula (II) includes an aminogroup or amino moiety being protected by a protecting group which can beremoved by hydrogenolysis, for example, benzyloxycarbonylamino, 3- or4-chlorobenzyloxycarbonylamino, 4-bromobenzyloxycarbonylamino,4-fluorobenzyloxycarbonylamino, 4-methylbenzyloxycarbonylamino, and4-methoxybenzyloxycarbonylamino. The protected carboxyl group orprotected carboxyl moiety for R₅₁ in the formula (II) includes acarboxyl group or carboxyl moiety being protected by a protecting groupwhich can be removed by hydrolysis or hydrogenolysis, for example, oneswhich are exemplified above in the explanation of the terms used in thepresent disclosure and claims.

The reaction of the compound (II) and the compound (III) is carried outunder atmospheric pressure or under pressure in a suitable solvent orwithout a solvent.

The solvent includes, for example, aromatic hydrocarbons (e.g. toluene,xylene), ketones (e.g. methyl ethyl ketone, methyl isobutyl ketone),ethers (e.g. dioxane, diglyme), alcohols (e.g. ethanol, isopropanol,butanol), acetonitrile, dimethylformamide, and dimethylsulfoxide. Thereaction is preferably carried out in the presence of a base, and thebase includes, for example, alkali metal carbonates (e.g. sodiumcarbonate, potassium carbonate), alkali metal hydrogen carbonates (e.g.sodium hydrogen carbonate, potassium hydrogen carbonate), and tertiaryamines (e.g. triethylamine), but the excess amount of the compound (III)may be used instead of a base. The reaction temperature varies accordingto the kinds of the starting compounds or the reaction conditions, butit is usually in the range of about 40° C. to about 200° C., morepreferably in the range of about 100° C. to about 170° C.

When R₃₁ and/or R₅₁ of the product thus obtained have a protectinggroup, these protecting groups may be removed by hydrogenolysis and/orhydrolysis.

The hydrogenolysis is carried out by a conventional method, for example,by reacting with hydrogen in a suitable solvent in the presence of acatalyst such as palladium-carbon, Raney-nickel, etc. The solventincludes, for example, alcohols (e.g. ethanol, methanol), water, aceticacid, dioxane and tetrahydrofuran. The reaction is usually carried outat a temperature of from about 0° C. to about 80° C., under atmosphericpressure or under pressure.

The hydrolysis is carried out by a conventional method, for example, bycontacting with water in a suitable solvent under acidic or basicconditions. The solvent includes, for example, alcohols (e.g. methanol,ethanol, isopropanol), dioxane, water, and a mixture of these solvents.The acid includes, for example, mineral acids (e.g. hydrochloric acid,sulfuric acid), and organic acids (e.g. formic acid, acetic acid,propionic acid, oxalic acid). The base includes, for example, alkalimetal hydroxides (e.g. sodium hydroxide, potassium hydroxide), andalkali metal carbonates (e.g. sodium carbonate, potassium carbonate).The reaction is usually carried out at a temperature of from about 20°C. to 100° C.

The starting compound (II) is prepared by subjecting a compound of theformula (IV): ##STR17## wherein Y is an oxygen atom or a sulfur atom,and R₅₁, R₆, R₇ and R₈ are the same as defined above, to halogenation orsulfonylation by a conventional method.

The halogenation is carried out by reacting the compound (IV) with ahalogenating agent (e.g. phosphorus oxychloride, phosphorus tribromide).The sulfonylation is carried out, for example, by reacting the compound(IV) wherein Y is an oxygen atom with a sulfonylating agent (e.g.methanesulfonyl chloride, p-toluenesulfonyl chloride,trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride).

The starting compound (IV) may be commercially available ones but can beprepared by a conventional method, for example, by the method disclosedin J. Am. Chem. Soc., 74, 842 (1952), Chem, Ber., 95, 937 (1962), J.Org. Chem., 29, 2887 (1964), or by the methods disclosed in thefollowing Reference Examples 1, 20 and 41-(1), -(3), or by a modifiedmethod thereof.

Another starting compound (III) is prepared by a conventional method,for example, by the method disclosed in Japanese Patent FirstPublication (Kokai) No. 32058/1990, or by the methods disclosed in thefollowing Reference Examples 45, 59 and 70, or by a modified methodthereof.

Process (b)

The compound of the formula (I) wherein X is --O-- and R₃ is a hydrogenatom is prepared by reacting a compound of the formula (II'): ##STR18##wherein Z₁ is a halogen atom, and R₅₁, R₆, R₇ and R₈ are the same asdefined above, with a compound of the formula (V): ##STR19## wherein R₁and R₂ are the same as defined above, and if necessary, followed byremoving the protecting groups from the product.

The reaction of the compound (II') and the compound (V) is carried outin the presence of a base in a suitable solvent or without a solventunder pressure or under atmospheric pressure. The solvent includes, forexample, toluene, xylene, dimethoxyethane, 1,2-dichloroethane, acetone,methyl ethyl ketone, dioxane, diglyme, ethyl acetate, dimethylformamideand dimethylsulfoxide. The base includes, for example, sodium hydride,triethylamine, potassium carbonate, and sodium carbonate. The reactionis usually carried out at a temperature of from about -10° C. to about150° C., preferably at a temperature of from about 10° C. to about 70°C.

When R₅₁ in the product thus obtained has a protecting group, theprotecting groups may be removed by hydrogenolysis or hydrolysis, in thesame manner as in above Process (a).

The starting compound (V) is prepared by subjecting a compound of theformula (VI): ##STR20## wherein R is a lower alkyl group, and R₁ and R₂are the same as defined above, to reduction by a conventional method.

The reduction of the compound (VI) is carried out in an alcohol (e.g.methanol, ethanol), an ether (e.g. tetrahydrofuran) or a mixture ofthese solvents, by using a reducing agent such as lithium borohydride,at a temperature of from about -5° C. to about 0° C.

The starting compound (VI) is prepared by a conventional method, or bythe method disclosed in the following Reference Example 81-(1), or by amodified method thereof.

Process (c)

The compound of the formula (I) wherein X is --O-- is prepared byreacting a compound of the formula (IVa): ##STR21## wherein R₅₁, R₆, R₇and R₈ are the same as defined above, with a compound of the formula(VII): ##STR22## wherein Z₁, R₁, R₂ and R₃₁ are the same as definedabove, if necessary, followed by removing the protecting groups from theproduct.

The reaction of the compound (IVa) and the compound (VII) is carried outin the same conditions such as solvent, base or reaction temperature, asthose in the above Process (b).

When R₃₁ and/or R₅₁ of the product have a protecting group, theprotecting groups may be removed by hydrogenolysis and/or hydrolysis inthe same manner as in above Process (a).

The compound (VII) is prepared by a conventional method, for example, bythe method disclosed in Japanese Patent First Publication (Kokai) No.64/1987, or by the method disclosed in the following Reference Example83, or by a modified method thereof.

Process (d)

The compound of the formula (I) is prepared by reacting a compound ofthe formula (VIII): ##STR23## wherein X, R₃₁, R₅₁, R₆, R₇ and R₈ are thesame as defined above, or a reactive derivative thereof, with a compoundof the formula (IX): ##STR24## wherein R₁ and R₂ are the same as definedabove, if necessary, followed by removing the protecting groups from theproduct.

The reactive derivative of the compound (VIII) includes, for example, alower alkyl ester (e.g. methyl ester), an active ester, an acidanhydride, and an acid halide (e.g. an acid chloride). The active esterincludes, for example, p-nitrophenyl ester, 2,4,5-trichlorophenyl ester,and N-hydroxysuccinimide ester. The acid anhydride includes, forexample, a symmetric acid anhydride and a mixed acid anhydride. Themixed acid anhydride includes, for example, a mixed acid anhydride withan alkyl chlorocarbonate such as ethyl chlorocarbonate, isobutylchlorocarbonate, a mixed acid anhydride with an aralkyl chlorocarbonatesuch as benzyl chlorocarbonate, a mixed acid anhydride with an arylchlorocarbonate such as phenyl chlorocarbonate, and a mixed acidanhydride with an alkanoic acid such as isovaleric acid and pivalicacid.

When the compound (VIII) per se is used, the reaction can be carried outin the presence of a condensing agent such asN,N'-dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride,N,N'-carbonyldiimidazole, N,N'-carbonyldisuccinimide,1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, diphenylphosphorylazide, propanesulfonic anhydride, andbenzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate.

The reaction of the compound (VIII) or a reactive derivative thereofwith the compound (IX) is carried out in a solvent or without a solvent.The solvent varies according to the kinds of the starting compounds,etc., but includes, for example, aromatic hydrocarbons (e.g. benzene,toluene, xylene), ethers (e.g. diethyl ether, tetrahydrofuran, dioxane),halogenated hydrocarbons (e.g. methylene chloride, chloroform), alcohols(e.g. ethanol, isopropanol), ethyl acetate, acetone, acetonitrile,dimethylformamide, dimethylsulfoxide, ethylene glycol, water, etc., andthese solvents may be used alone, or in the form of a mixture of two ormore solvents. The reaction is carried out in the presence of a base ifnecessary, and the base includes, for example, alkali metal hydroxides(e.g. sodium hydroxide, potassium hydroxide), alkali metal carbonates(e.g. sodium carbonate, potassium carbonate), alkali metal hydrogencarbonates (e.g. sodium hydrogen carbonate, potassium hydrogencarbonate), and organic bases such as triethylamine, tributylamine,diisopropylethylamine, N-methylmorpholine, but the excess amount of thecompound (IX) may be used instead of a base. The reaction temperaturevaries according to the kinds of the starting compounds, but it isusually in the range of about -30° C. to about 200° C., preferably inthe range of about -10° C. to about 150° C.

When R₃₁ and/or R₅₁ of the product thus obtained have a protectinggroup, these protecting groups may be removed by hydrogenolysis and/orhydrolysis, in the same manner as in above Process (a).

The compound of the formula (VIII) wherein X is an oxygen atom isprepared, for example, by above Process (c), i.e. by reacting the abovecompound (IVa) with a compound of the formula (X): ##STR25## wherein Z₁,R and R₃₁ are the same as defined above, in the same manner as inProcess (c), followed by subjecting the product to hydrolysis in aconventional manner.

The compound of the formula (X) is commercially available ones but canbe prepared by a conventional manner.

The compound of the formula (VIII) wherein X is --NH₄ -- is prepared,for example, by above Process (a), i.e. by reacting the compound (II)with a compound of the formula (XI): ##STR26## wherein R' is a loweralkyl group, benzyl group or a benzyl group being substituted by ahalogen atom, methyl group or methoxy group, and R₃₁ and R₄ are the sameas defined above, in the same manner as in Process (a), followed bysubjecting the product to hydrolysis or hydrogenolysis in a conventionalmanner.

The compound (XI) is commercially available ones but can be prepared bya conventional method.

Process (e)

The compound of the formula (I) wherein R₁ is a lower alkyl group, alower alkenyl group or a cycloalkyl-lower alkyl group is prepared byreacting a compound of the formula (XII): ##STR27## wherein X, R₂, R₃,R₅, R₆, R₇ and R₈ are the same as defined above, with a compound of theformula (XIII):

    R.sub.11 --Z.sub.1                                         (XIII):

wherein R₁₁ is a lower alkyl group, a lower alkenyl group or acycloalkyl-lower alkyl group, and Z₁ is the same as defined above, ifnecessary, followed by removing the protecting groups from the product.

The reaction of the compound (XII) and the compound (XIII) is usuallycarried out in a suitable solvent. The solvent includes, for example,aromatic hydrocarbons (e.g. benzene, xylene), ketones (e.g. methyl ethylketone), ethers (e.g. dioxane), and dimethylformamide. The reaction ispreferably carried out in the presence of a base, and the base includesones exemplified above in Process (a), and sodium hydride. The reactiontemperature varies according to the kinds of the starting compounds orthe reaction conditions, but it is usually in the range of about 0° C.to about 200° C., and when sodium hydride is used as a base, it is inthe range of about 0° C. to about 50° C.

When R₃₁ and/or R₅₁ of the product have a protecting group, theprotecting groups may be removed by hydrogenolysis and/or hydrolysis.

The compound (XII) is prepared by using the compound (VIII) and thecompound (IX) wherein R₁ is a hydrogen atom in above Process (d).

The compound (XIII) may be commercially available ones but can beprepared by a conventional method.

In above Processes (a) to (e), when the starting compounds used thereinhave a group which may participate in the reaction, it is convenient toprotect said group with a protecting group, or to convert it previouslyinto a group which can easily be converted into said group after thereaction. For example, a part of the compound (I) is prepared by thefollowing processes.

The compound of the formula (I) wherein R₅ is an amino group is preparedby subjecting the compound (I) wherein R₅ is a nitro group to reductionby a conventional method. This process is explained below in Examples122 and 124.

The compound of the formula (I) wherein R₅ is an acylamino group isprepared by reacting the compound (I) wherein R₅ is an amino group witha corresponding carboxylic acid or a reactive derivative thereof. Thisprocess is explained below in Example 125.

The compound of the formula (I) wherein R₅ is a hydroxy-lower alkylgroup is prepared by subjecting the compound (I) wherein R₅ is analkoxycarbonyl group or an alkoxycarbonyl-lower alkyl group wherein thealkyl moiety has carbon atoms fewer by one carbon atom, to reduction bya conventional method. This process is explained below in Example 127.

The compound of the formula (I) wherein R₈ is a hydroxy group isprepared by treating the compound (I) wherein R₈ is a methoxy group withhydrogen bromide.

The desired compounds obtained in the above Processes can be isolatedand purified by a conventional method such as chromatography,recrystallization, re-precipitation, etc. The compound (I) which showsbasicity enough to form an acid addition salt thereof is converted intoan acid addition salt thereof by treating it with various acids by aconventional method.

Various stereoisomers of the compound (I) can be separated and purifiedby a conventional method such as chromatography, etc.

The pharmacological activities of the present compounds are explained bythe following pharmacological experiments on the representativecompounds of the present invention.

Experiment 1: Central (ω₁, ω₂) and peripheral (ω₃) benzodiazepine (BZ)receptor binding assays

BZω₁ and BZω₂ receptor binding assays were carried out according to themethod of Stephens, D. N. et al. [cf. J. Pharmacol. Exp. Ther. 253,334-343 (1990)], and BZω₃ receptor binding assay was done according tothe method of Schoemaker, H. [cf. J. Pharmacol. Exp. Ther. 225, 61-69(1983)] each with slight modification.

Receptor membrane fractions for ω₁, ω₂ and ω₃ were prepared from thecerebellum (ω₁), spinal cord (ω₁) or kidney (ω₃) in 7-8 week old malerats of Wistar strain by the procedure described below.

After the cerebellum or spinal cord was homogenized with 20 volumes ofice-cold 50 mM Tris-citrate buffer (pH 7.1), the homogenate wascentrifuged for 15 minutes at 40,000 g. The pellet obtained was washed 4times by the same procedure, frozen and stored for 24 hours at -60° C.The resulting pellet, after being thawed, washed with the buffer andcentrifuged, was suspended in the buffer I for the binding assay (50 mMTris-HCl buffer containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl₂ and 1 mMMgCl₂ ; pH 7.4) and the suspension thus obtained (containing 1 g wettissue/40 ml) was used for the BZω₁ and BZω₂ receptor binding assays. Onthe other hand, the kidney was homogenized with 20 volumes of theice-cold buffer II for the binding assay (50 mM Na--K phosphate buffercontaining 100 mM NaCl; pH 7.4), filtered through 4 sheets of gauze, andcentrifuged for 20 minutes at 40,000 g. The pellet obtained wassuspended in the buffer II and the suspension (containing 1 g wettissue/100 ml) was used for the binding assay as BZω₃ receptor membranesource.

[³ H] Flumazenil (final concentration: 0.3 nM for (ω₁ and 1 nM for ω₂)and flunitrazepam (final concentration: 10 μM) were used for the BZω₁ orBZω₂ receptor binding assays as the isotope-labeled and unlabeledligands, respectively. For the BZω₃ receptor binding assay, [³ H]4'-chlorodiazepam(7-chloro-1,3-dihydro-1-methyl-5-(4-chlorophenyl)-2H-1,4-benzodiazepin-2-one)(final concentration: 0.5 nM) and diazepam (final concentration: 100 μM)were used as the isotope-labeled and unlabeled ligands, respectively.Incubation was performed for 30 minutes at 37° C. in the BZω₁ or BZω₂receptor binding assays, and for 150 minutes at 0° C. in the BZω₃receptor binding assay. The BZω₁ or BZω₂ receptor binding assays werecarried out in the presence of bicuculline (final concentration: 100μM).

The binding assay was performed by the following procedure. After addingeach test compound at certain known concentrations, a [³ H] ligand andthe buffer I or II to each test tube, each assay was started by additionof membrane preparation (total volume of 1 ml). After incubation, theassay was terminated by filtration with suction through a Whatman GF/Bglass fiber filter using a cell harvester (Brandel, USA). The filterswere rapidly washed 3 times with 5 ml of ice-cold 50 mM Tris-HCl buffer(pH 7.7) for ω₁ and ω₂, or the buffer II forω₃, and transferred toscintillation vials containing 10 ml liquid scintillation cocktail(ACS-II, Amersham, USA). After a few hours, retained radioactivity wascounted by a liquid scintillation spectrometer. Specific binding of [³H] ligands was calculated as the difference between amounts ofradioactivity bound in the presence and absence of excess unlabeledligands. The concentration of the test compounds causing 50% inhibitionof specific binding of the [³ H] ligand (IC₅₀) was determined by probitanalysis. The results of benzodiazepineω₃ receptor binding assay areshown in Table 5. It is noted that all the compounds listed in Table 5had affinity for the BZω₁ and BZω₂ receptors with IC₅₀ values largerthan 1000 nM.

                  TABLE 5                                                         ______________________________________                                                       ω.sub.3                                                         Test Comp.                                                                            IC.sub.50 (nM)                                                 ______________________________________                                                 1*    3.10                                                                   2      0.97                                                                   4      4.36                                                                   5      1.28                                                                   6      0.23                                                                   10     0.70                                                                   15     3.86                                                                   16     4.00                                                                   17     1.97                                                                   22     3.26                                                                   23     1.76                                                                   25     1.93                                                                   26     0.28                                                                   27     0.11                                                                   29     0.85                                                                   35     1.51                                                                   36     1.44                                                                   37     1.66                                                                   41     2.53                                                                   42     2.15                                                                   44     4.98                                                                   45     0.70                                                                   47     0.16                                                                   49     0.23                                                                   51     0.32                                                                   52     29.5                                                                   57     5.39                                                                   58     1.62                                                                   61     9.80                                                                   65     1.66                                                                   68     2.19                                                                   69     2.75                                                                   70     1.12                                                                   76     1.33                                                                   79     0.87                                                                   81     6.90                                                                   83     5.02                                                                   84     2.04                                                                   85     0.18                                                                   93     4.10                                                                   97     2.27                                                                  102     3.31                                                                  103     2.90                                                                  104     3.44                                                                  105     4.18                                                                  106     4.24                                                                  107     4.23                                                                  108     1.21                                                                  109     2.09                                                                  110     1.99                                                                  111     2.05                                                                  112     2.34                                                                  118     1.07                                                                  119     1.45                                                                  120     1.63                                                                  124     5.35                                                                  127     4.35                                                                  128     0.79                                                                  130     1.31                                                                  131     0.89                                                                  133     2.20                                                                  134     3.07                                                                  135     3.17                                                                  136     0.34                                                                  137     0.93                                                                  138     0.53                                                                  139     0.38                                                                  141     0.11                                                                  142     0.08                                                                  143     1.40                                                                  144     0.31                                                                  145     1.60                                                                  147     0.52                                                                  149     1.14                                                                  151     0.58                                                                  155     0.76                                                                  156     4.96                                                                  158     4.07                                                                  159     2.00                                                                  160     4.30                                                                  161     1.05                                                                  162     1.19                                                                  163     2.64                                                                  164     0.29                                                                  165     5.07                                                                  166     5.40                                                                  167     0.79                                                                  168     0.99                                                                  169     1.15                                                                  170     0.99                                                                  171     1.56                                                                  175     1.90                                                                  178     0.57                                                                  179     4.30                                                                  180     1.65                                                                  181     1.61                                                                  182     4.57                                                                  183     8.75                                                                  184     0.82                                                                  186     2.39                                                                  187     9.71                                                                  188     5.24                                                                  190     4.00                                                                  195     2.00                                                           ______________________________________                                         *The compound of Example 1 (hereinafter, the compounds of Examples in the     same way)                                                                

The compounds listed in Table 5 bind strongly to the BZω₃ receptor, buthave affinity for the BZω₁ and Bω₂ receptors with the IC₅₀ value largerthan 1000 nM. Therefore, it is evident that the compounds of the presentinvention have potent and highly selective affinity for the BZω₃receptor.

Experiment 2: Light and dark box test (anti-anxiety effect)

Anti-anxiety effect of test compounds was examined in a box with lightand dark compartments according to the method of Crawley, J. andGoodwin, F. K. [cf. Pharmacol. Biochem. Behav. 13, 167-170 (1980)] withslight modification.

Light and dark box test is a useful, simple and handy method forbehaviorally and pharmacologically examining anti-anxiety effect of thedrugs, by utilizing the habit of rodents such as mice and rats, etc.which prefer to stay in a dark place, and regarding as positive drugeffect the increase of the relative stay of the animals in the lightcompartment which is an uncomfortable place for the animals. A number ofdrugs such as cholecystokinin B type receptor antagonists and BZanxiolytics, etc. show positive effect in this test.

Light and dark box test was carried out using the test box device(35×15×17 cm) which comprises: a light compartment (20×15×17 cm)consisting of transparent acrylic plates and highly illuminated by anincandescent lamp (1,700 lux); a dark compartment (15×15×17 cm) beingmade of black acrylic plates connected to the light compartment; and atthe boundary of compartments, an opening (4.4×5 cm) in which mice can gothrough freely between two compartments.

Male mice of Std-ddY strain weighing 25-30 g were used in a group of 10.Each trial was started by placing a mouse in the center of the lightcompartment 30 minutes after oral administration of a test compound, andthe time spent by the mouse in the light compartment during a 5 minuteobservation period was measured, and the rate of the stay of mice in thelight compartment to the whole time spent in the experiment wascalculated. The increasing rate of the relative stay of the testcompound to that of the vehicle control group was yielded, based on therate of the stay of mice in the light compartment.

The anti-anxiety effect of the test compound was represented by theminimum effectivetive dose (MED) at which the increasing rate of therelative stay was regarded statistically as significant(Williams-Wilcoxon's test, p<0.05). The results are shown in Table 6.

                  TABLE 6                                                         ______________________________________                                                     Anti-anxiety effect                                              Test Comp.   MED (mg/kg)                                                      ______________________________________                                         1*          0.3                                                               2           0.01                                                              6           0.3                                                               9           0.3                                                              10           1.0                                                              16           0.1                                                              21           0.1                                                              22           0.3                                                              23           0.01                                                             29           0.03                                                             31           0.3                                                              35           0.1                                                              36           0.3                                                              37           0.1                                                              42           <0.01                                                            45           0.1                                                              52           0.1                                                              136          0.3                                                              139          0.1                                                              150          0.3                                                              ______________________________________                                         *The compound of Example 1 (hereinafter, the compounds of Examples in the     same way)                                                                

Test compounds in Table 6 have anti-anxiety effect at doses of 1 mg/kgor below. Among them, many compounds are effective at doses of 0.3 mg/kgor

Experiment 3: Isoniazid-induced clonic convulsion test (anti-convulsanteffect)

Isoniazid inhibits glutamate decarboxylase which catalyzes GABAsynthesis, deases brain GABA levels, and induces clonic convulsion.According to the method of Auta, J. et al. [cf. J. Pharmacol. Exp. Ther.265, 649-656 (1993)] with slight modification, we examined antagonisticeffect of the test compounds on isoniazid-induced clonic convulsion.Many drugs which, directly or indirectly, enhance GABA_(A) receptorfunction are known to exhibit positive effect in this test. Those are BZanxiolytics represented by diazepam, neurosteroids such asallopregnanolone, allotetrahydrodeoxycortico-sterone(THDOC) and BZω₃receptor agonists which enhance the synthesis of neurosteroids.

Male mice of Std-ddY strain weighing 22-24 g were used in a group of 6.Thirty minutes after oral administration of the test compounds, micewere injected with isoniazid (200 mg/kg, s.c.), and immediatelythereafter, placed individually in acrylic observation cages. The onsettime of clonic convulsion was measured (cut-off time: 90 minutes). Thelatency in the control group was about 40 minutes.

Anti-isoniazid effect of the test compounds was expressed as the dosewhich prolonged the onset time by 25% compared to that in the vehiclegroup (ED₂₅). The ED₂₅ value was calculated according to theLitchfield-Wilcoxon's method. The results are shown in Table 7.

                  TABLE 7                                                         ______________________________________                                                     Anti-isoniazid effect                                            Test Comp.   ED.sub.25 (mg/kg)                                                ______________________________________                                         1*          82.2                                                              2           65.6                                                              4           51.2                                                              5           15.1                                                              9           25.5                                                             10           36.9                                                             11           47.5                                                             12           31.8                                                             17           45.7                                                             21           72.1                                                             22           50.3                                                             23           40.8                                                             25           62.1                                                             29           67.5                                                             35           85.7                                                             36           54.2                                                             37           61.9                                                             42           58.7                                                             44           22.4                                                             45           9.60                                                             47           7.62                                                             48           7.67                                                             50           27.3                                                             52           23.5                                                             53           11.3                                                             58           11.8                                                             59           14.8                                                             60           2.14                                                             61           17.7                                                             65           31.1                                                              66a         51.2                                                              66b         72.4                                                             79           43.8                                                             83           70.2                                                             171          76.4                                                             ______________________________________                                         *The compound of Example 1 (hereinafter, the compounds of Examples in the     same way)                                                                

The test compounds in Table 7 exhibited anti-convulsant effect at doseslower than 100 mg/kg. Some of them caused the effect at doses below 10mg/kg.

Experiment 4: Collagen-induced arthritis inhibitory test 1

Collagen-induced arthritis inhibitory test is an experimental model forrheumatoid arthritis reported by Trethan, D. E. et al. [cf. J. Exp.Med., 146, 857 (1977)], and thereafter Kakimoto, K. et al. demonstratedthat collagen-induced arthritis inhibitory test was useful as anevaluating tool for not only anti-inflammatory agents, but also immunosuppressing agents and immuno modulating agents, based on the mechanismof onset of the disease [cf. J. Immunol., 140, 78-83 (1988)].

Collagen-induced arthritis inhibitory test was carried out according toKakimoto, K. et al. (cf. above reference of Kakimoto, K. et al.) withslight modification. Solubilized bovine cartilage type II collagen(product of Elastine Products, U.S.A.) was emulsified in completeFreund's adjuvant (product of DIFCO Lab., U.S.A.). Male mice of DBA/1jstrain (6 week-old; product of Nippon Charles River, Japan) wereimmunized by injection at the base of the tail with 150 μg of theemulsified collagen. After twenty one days from the immunization,arthritis was induced by a booster immunization of 150 μg of theemulsified collagen prepared in the same manner as above at the base ofthe tail again. A test compound was orally administered daily at thedose of 10 mg/kg from the first immunization. Mice were observed daily 5days after the booster immunization for the onset of arthritis, and anarthritic score was derived by grading the severity of involvement ofeach paw five scales (0-4) according to the method of Wood, F. D. et al.[cf. Int. Arch. Allergy Appl. Immunol., 35, 456-467 (1969)] with slightmodification as shown in Table 8. The severity of arthritis wasestimated by the sum of the scores of all 4 paws, and the onset of thedisease was determined when score 1 was observed.

                  TABLE 8                                                         ______________________________________                                        Score Symptoms                                                                ______________________________________                                        0     No changes                                                              1     Erythema and swelling of one interphalangeal joint of the fingers             of 4 paws                                                               2     Erythema and swelling of two or more interphalangeal joints, or               relatively large joints of wrist, ankle, etc.                           3     Gross swelling and erythema                                             4     Reaching the maximum level of swelling of the entire                    ______________________________________                                              paw                                                                 

In the mice which were administered with the compound of Example 93, theonset of arthritis was delayed until 40 days, after the boosterimmunization, while in the control mice which were injected with thesolvent, the onset of arthritis was observed on 28th day. In the micewhich were administered with the compound of Example 136 and Example144, the onset of arthritis was delayed until 34 days and 37 days,respectively, after the booster immunization. The severity of arthritisin the compound-treated group (Example 93, 136 and 144) was much lowerthan the control group in the severity of the disease judging from thescore of arthritis.

Experiment 5: Collagen-induced arthritis inhibitory test 2

Collagen-induced arthritis inhibitory test was carried out according toKakimoto, K. et al. (cf. above reference of Kakimoto, K. et al.) withslight modification. Type II collagen from bovine joints (product of theCollagen Research Center, Japan) was emulsified in complete Freund'sadjuvant (product of DIFCO Lab., U.S.A.). Female mice of DBA/1j strain(product of Nippon Charles River, Japan) were immunized by injection atthe base of the tail with 150 μg of the emulsified collagen. Aftertwenty one days from the immunization, arthritis was induced by abooster immunization of 150 μg of the emulsified collagen prepared inthe same manner as above at the base of the tail again. Test compoundswere administered orally at a dose of 10 mg/kg on 5 consecutive days ina week for 8 weeks, beginning from the day before the immunization. Micewere monitored visually for arthritis once a week beginning from the dayof the booster immunization. Each paw was individually scored on a scaleof 0-3, according to the criteria shown in Table 9. The severity ofarthritis was estimated by the sum of the scores of all 4 paws.

                  TABLE 9                                                         ______________________________________                                        Score                                                                              Symptoms                                                                 ______________________________________                                        0    No changes                                                               1    Erythema and swelling of one or more interphalangeal joints of the            paw                                                                      2    Erythema and swelling of two or more large joints which extends               to the back of the paw in addition to Erythema and swelling of one            or more interphalangeal joints of the paw                                3    Severe erythema and swelling of the entire paw                           ______________________________________                                    

In the mice which were administered with the compound of Example 6, theonset of arthritis was delayed until 21 days after the boosterimmunization as compared with the control mice which were injected withthe solvent, and the severity of arthritis in the compound-treated groupwas much lower than the control group at least until day 34, the lastday of the experiment. The compound of Example 165 markedly suppressedthe arthritis as compared with control group, at least until 34th day,the last day of the experiment. In the mice which were administered withthe compound of Example 178, the arthritis was suppressed as comparedwith the control.

From the results clearly shown in the above experiments 4 and 5, thecompounds of Examples 6, 93, 136, 144 and 165 exhibit potent effect oncollagen-induced arthritis inhibitory test which is a model for immunoinflammatory diseases (rheumatoid arthritis, etc.). The compound ofExample 178 has also effect, but less potent effect as compared withthat of each compound as indicated above.

Experiment 6: Acute toxicity

Male mice of Std-ddY strain weighing 24-31 g were used in a group of 10for examining acute toxicity of test compounds (Example 2, 10, 23, 36,42 and 52). A compound (1000 mg/kg) was suspended in 0.5% tragacanth andadministered orally or intraperitoneally. Then, lethality of the micewas observed for 7 days after the treatment.

No lethality was found in mice to which the test compound wasadministered.

The compound of formula (I) and its pharmaceutically acceptable saltsnot only bind to the BZω₃ receptor selectively and strongly, but alsoproduce excellent pharmacological effects such as anti-anxiety effectand anti-convulsant effect, etc. in animal experiment, therefore, areuseful for the therapy or prevention of CNS diseases [anxiety-relateddiseases (neurosis, somatoform disorders, other anxiety disorders),depression, epilepsy, etc.] and cardiovascular diseases (cardiac angina,hypertension, etc.).

There are listed, for example, the following compounds andpharmaceutically acceptable salts thereof which show not only selectiveand strong affinity for BZω₃ receptor, but also strong anti-anxietyeffect.

(1)2-[2-(4-Chlorophenyl)-5,6-dimethyl-4-pyrimidinylamino]-N,N-dipropylacetamide(the compound of Example 2)

(2)2-[2-(4-Chlorophenyl)-5,6-dimethyl-4-pyrimidinylamino]-N-methyl-N-phenylacetamide(the compound of Example 23)

(3)2-[2-(4-Chlorophenyl)-5,6-dimethyl-4-pyrimidinylamino]-N,N-diethylacetamide(the compound of Example 10)

(4)N-(4-Chlorophenyl)-N-methyl-2-(5,6-dimethyl-2-phenyl-4-pyrimidinylamino)acetamide (the compound of Example 29)

(5)2-[2-(4-Chlorophenyl)-5,6-dimethyl-4-pyrimidinylamino]-N-(4-fluorophenyl)-N-methylacetamide(the compound of Example 36)

(6)2-[2-(4-Chlorophenyl)-5,6-dimethyl-4-pyrimidinylamino]-N-(4-methoxyphenyl)-N-methylacetamide(the compound of Example 42)

(7)2-(5,6-Dimethyl-2-phenyl-4-pyrimidinylamino)-N-phenyl-N-propylacetamide(the compound of Example 52)

(8)2-[2-(4-Chlorophenyl)-5,6-dimethyl-4-pyrimidinylamino]-N-ethyl-N-phenylacetamide(the compound of Example 45)

The compounds of formula (I) have inhibitory effect on collagen-inducedarthritis, therefore, are useful for the therapy or prevention of immunediseases such as immuno inflammatory diseases (rheumatoid arthritis,etc.) and immunoneurologic diseases (multiple sclerosis, etc.).

There are listed, for example, the following compounds andpharmaceutically acceptable salts thereof which show inhibitory effecton collagen-induced arthritis.

(1) 2-(5,6-Dimethyl-2-phenyl-4-pyrimidinyloxy)-N,N-dipropylacetamide(the compound of Example 136)

(2) 2-(2,6-Diphenyl-4-pyrimidinylamino)-N,N-dipropylacetamide (thecompound of Example 93)

(3)2-[5,6-Dimethyl-2-(4-trifluoromethylphenyl)-4-pyrimidinylamino]-N,N-dipropylacetamide(the compound of Example 6)

(4)2-[2-(4-Aminophenyl)-5,6-dimethyl-4-pyrimidinyloxy]-N-ethyl-N-phenylacetamide(the compound of Example 165)

(5)2-[2-(4-Chlorophenyl)-5,6-dimethyl-4-pyrimidinyloxy]-N-methyl-N-phenylacetamide(the compound of Example 144)

(6)2-(5,6-Dimethyl-2-phenyl-4-pyrimidinyloxy)-N-phenyl-N-propylacetamide(the compound of Example 178)

The compounds [I] of the present invention or a pharmaceuticallyacceptable acid addition salt thereof can be administered either orally,parenterally or rectally. The dose of the compounds of the presentinvention varies according to the kinds of the compound, theadministration routes, the conditions, ages of the patients, etc., butit is usually in the range of 0.01-50 mg/kg/day, preferably in the rangeof 0.03-5 mg/kg/day.

The compounds of the present invention is usually administered in theform of a pharmaceutical preparation which is prepared by mixing thereofwith a pharmaceutically acceptable carrier or diluent. Thepharmaceutically acceptable carrier or diluent may be any conventionalones which are usually used in the pharmaceutical field, and do notreact with the compounds of the present invention. Suitable examples ofthe pharmaceutically acceptable carrier or diluent are, for example,lactose, inositol, glucose, mannitol, dextran, cyclodextrin, sorbitol,starch, partly pregelatinized starch, white sugar, magnesiummetasilicate aluminate, synthetic aluminum silicate, crystallinecellulose, sodium carboxymethylcellulose, hydroxypropyl starch, calciumcarboxylmethylcellulose, ion exchange resin, methylcellulose, gelatin,gum arabic, hydroxypropyl cellulose, low substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinylalcohol, alginic acid, sodium alginate, light anhydrous silicic acid,magnesium stearate, talc, carboxyvinyl polymer, titanium oxide, sorbitanfatty acid ester, sodium laurylsulfate, glycerin, glycerin fatty acidester, purified lanolin, glycerogelatin, polysorbate, macrogol,vegetable oil, wax, propyleneglycol, water, ethanol,polyoxyethylenehydrogenated caster oil (HCO), sodium chloride, sodiumhydroxide, hydrochloric acid, disodium hydrogen phosphate, sodiumdihydrogen phosphate, citric acid, glutamic acid, benzyl alcohol, methylp-oxybenzoate, ethyl p-oxybenzoate, etc.

The pharmaceutical preparation is, for example, tablets, capsules,granules, powders, syrups, suspensions, suppositories, injectionpreparations, etc. These preparations may be prepared by a conventionalmethod. In the preparation of liquids, the compound of the presentinvention may be dissolved or suspended in water or a suitable othersolvent, when administered. Tablets and granules may be coated by aconventional method. In the injection preparations, it is preferable todissolve the compound of the present invention in water, but ifnecessary, it may be dissolved by using an isotonic agent or asolubilizer, and further, a pH adjustor, a buffering agent or apreservative may be added thereto.

These preparations may contain the compound of the present invention ata ratio of at least 0.01%, preferably at a ratio of 0.1-70%. Thesepreparations may also contain other therapeutically effective compoundsas well.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is illustrated in more detail by the followingReference Examples and Examples, but should not be construed to belimited thereto.

The identification of the compounds is carried out by Elementaryanalysis, Mass spectrum, IR spectrum, NMR spectrum, etc.

The following abbreviations may be used in the following ReferenceExamples and Examples in order to simplify the disclosure.

[Solvent for recrystallization]

A: Ethanol

AC: Acetonitrile

E: Diethyl ether

EA: Ethyl acetate

HX: n-Hexane

IP: Isopropanol

M: Methanol

REFERENCE EXAMPLE 1

Preparation of 5,6-dimethyl-2-phenyl-4(3H)-pyrimidinone:

To a mixture of sodium ethoxide (31.3 g) and anhydrous ethanol (200 ml)is added benzamidine hydrochloride (23.9 g) at 0-5° C. The mixture isstirred at 0° C. for 30 minutes, and thereto is added dropwise asolution of ethyl 2-methylacetoacetate (20 g) and anhydrous ethanol (50ml) at the same temperature. After addition, the mixture is stirred atroom temperature for 30 minutes, and refluxed for six hours. Thereaction mixture is concentrated under reduced pressure, and the residueis dissolved in water. The pH value of the mixture is adjusted to pH 4by addition of conc. hydrochloric acid while the mixture is stirred at0-5° C. The precipitates are collected by filtration, washed with water,further washed with diethyl ether, and recrystallized from ethanol togive the desired compound (14.3 g), m.p. 205-207° C.

REFERENCE EXAMPLES 2-19

The corresponding starting compounds are treated in the same manner asin Reference Example 1 to give the compounds as listed in Table 10.

                  TABLE 10                                                        ______________________________________                                        5 #STR28##                                                                                                   M.p.     Solv. for                             Ref. Ex.                                                                              R.sub.5  R.sub.6 R.sub.7                                                                             (°C.)                                                                           recrystal.                            ______________________________________                                        2       Me       Me      4-Cl  258-260  M                                     3       Me       Me      3-Cl  251-252  A                                     4       Me       Me      4-F   266-268  M                                     5       Me       Me      4-OMe 233-235  M                                     6       Me       Me      4-CF.sub.3                                                                          265-267  M                                     7       Me       Me      4-NO.sub.2                                                                          >300     M                                     8       Me       Et      H     195-197  M                                     9       Me       i-Pr    H     230-232  M                                     10      Et       Me      H     159-161  A                                     11      H        Me      H     212-214  A                                     12      H        CF.sub.3                                                                              H     228-230  A                                     13      H        Ph      H     281-284  A                                     14      H        Ph      4-Cl  >300     M                                     15      Me       Ph      H     250-252  M                                     16      Me       Ph      4-Cl  293-295  M                                     17      --(CH.sub.2).sub.4 --                                                                      H       223-225  A                                       18      --(CH.sub.2).sub.4 --                                                                      4-Cl    290-292  M                                       19      COOEt    H       H     237-238  A                                     ______________________________________                                    

REFERENCE EXAMPLE 20

Preparation of 5-nitro-2-phenyl-4(3H)-pyrimidinone:

To a mixture of sodium methoxide (8 g) and anhydrous ethanol (100 ml) isadded benzamidine hydrochloride (11.7 g) at 0° C. The mixture is stirredat 0° C. for 30 minutes, and thereto is added dropwise a solution ofcrude ethyl 2-(N,N-dimethylaminomethylene)nitroacetate (14 g), which isobtained by refluxing a mixture of ethyl nitroacetate (10 g) andN,N-dimethylformamide dimethyl acetal (10.7 g) for three hours, followedby concentrating the mixture under reduced pressure, in anhydrousethanol (50 ml) at the same temperature. After addition, the mixture isstirred at room temperature for 30 minutes, and refluxed for 12 hours.The reaction mixture is concentrated under reduced pressure, and water(150 ml) is added to the residue. The pH value of the mixture isadjusted to pH 4 by addition of conc. hydrochloric acid while themixture is stirred at 0° C. The precipitates are collected byfiltration, washed with water, and recrystallized from ethanol to givethe desired compound (7 g), m.p. 264-266° C.

REFERENCE EXAMPLE 21

Preparation of 4-chloro-5,6-dimethyl-2-phenylpyrimidine:

A mixture of 5,6-dimethyl-2-phenyl-4(3H)-pyrimidine (10 g) andphosphorus oxychloride (23 g) is stirred at 75° C. for four hours. Thereaction mixture is concentrated under reduced pressure, and the residueis dissolved in chloroform. To the mixture is added ice-water, and themixture is stirred. The mixture is neutralized with 1N aqueous sodiumhydroxide solution, and the chloroform layer is collected, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue is recrystallized from ethanol to give the desired compound(10.7 g), m.p. 120-122° C.

REFERENCE EXAMPLES 22-40

The corresponding starting compounds are treated in the same manner asin Reference Example 21 to give the compounds as listed in Table 11.

                  TABLE 11                                                        ______________________________________                                        6 #STR29##                                                                                                   M.p.     Solv. for                             Ref. Ex.                                                                              R.sub.5  R.sub.6 R.sub.7                                                                             (°C.)                                                                           Recrystal.                            ______________________________________                                        22      Me       Me      4-Cl  122-124  IP                                    23      Me       Me      3-Cl  96-97    A                                     24      Me       Me      4-F   138-139  IP                                    25      Me       Me      4-OMe 106-108  IP                                    26      Me       Me      4-CF.sub.3                                                                          70-71    IP                                    27      Me       Me      4-NO.sub.2                                                                          157-158  A                                     28      Me       Et      H     87-88    IP                                    29      Me       i-Pr    H     83-84    IP                                    30      Et       Me      H     57-58    IP                                    31      H        Me      H     62-63    IP                                    32      H        CF.sub.3                                                                              H     45-46    IP                                    33      H        Ph      H      99-100  IP                                    34      H        Ph      4-Cl  125-126  IP                                    35      Me       Ph      H     116-117  IP                                    36      Me       Ph      4-Cl  126-128  IP                                    37      --(CH.sub.2).sub.4 --                                                                      H       100-101  IP                                      38      --(CH.sub.2).sub.4 --                                                                      4-Cl    114-115  IP                                      39      NO.sub.2 H       H     160-161  A                                     40      COOEt    H       H     39-40    HX                                    ______________________________________                                    

REFERENCE EXAMPLE 41

Preparation of4-chloro-2-(4-fluorophenyl)-5,6,7,8-tetrahydroquinozoline:

(1) A mixture o 4-fluorobenzoyl chloride (50 g), potassium thiocyanate(36.7 g) and anhydrous toluene (100 ml) is refluxed for six hours. Aftercooling, the reaction mixture is filtered, and the filtrate isconcentrated under reduced pressure. The residue is purified bydistillation under reduced pressure to give 4-fluorobenzoylisothiocyanate (55 g), b.p. 92° C/3 mmHg.

(2) To a mixture of the above product (62 g) and chloroform (80 ml) isadded dropwise a solution of 1-morpholinocyclohexene (28.6 g) andchloroform (30 ml) with stirring while the temperature of the mixture iskept at 0-5° C. After addition, the reaction mixture is stirred at 0° C.for one hour, and further stirred at room temperature for one hour, andrefluxed for one hour. The reaction mixture is concentrated underreduced pressure, and the residue is purified by silica gel columnchromatography (eluent; chloroform), and recrystallized from ethanol togive 2-(4-fluorophenyl)-5,6,7,8-tetrahydro-4H-1,3-benzoxazine-4-thione(24 g), m.p. 148-149° C.

(3) Into a mixture of the above product (20 g) and methanol (300 ml) isblown ammonia gas for 30 minutes, and the mixture is stirred at 80° C.for 30 minutes. The reaction mixture is concentrated under reducedpressure, and the residue is recrystallized from ethanol to give2-(4-fluorophenyl)-5,6,7,8-tetrahydro-4(3H)-quinazolinethione (18 g),m.p. 198-200° C.

(4) A mixture of the above product (10 g) and phosphorus oxychloride (30g) is refluxed for two hours. The reaction mixture is concentrated underreduced pressure, and the residue is dissolved in chloroform. To themixture is added ice-water, and the mixture is stirred. The chloroformlayer is collected, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue is recrystallized fromisopropanol to give the desired compound (8.5 g), m.p. 96-97° C.

REFERENCE EXAMPLES 42-44

The same procedures as Reference Example 41 are repeated except that thecorresponding starting compounds are used instead of 4-fluorobenzoylchloride to give the following compounds.

(Reference Example 42)

4-Chloro-2-(2-chlorophenyl)-5,6,7,8-tetrahydroquinazoline; m.p. 79-80°C.

(Reference Example 43)

4-Chloro-2-(3-chlorophenyl)-5,6,7,8-tetrahydroquinazoline; m.p. 94-95°C.

(Reference Example 44)

4-Chloro-2-(2,4-difluorophenyl)-5,6,7,8-tetrahydroquinazoline; m.p.57-58° C.

REFERENCE EXAMPLE 45

Preparation of 2-amino-N,N-dipropylacetamide:

(1) To a mixture of dipropylamine (5 g), triethylamine (5 g) andmethylene chloride (50 ml) is added dropwise a solution ofN-phthaloylglycyl chloride (11 g) in methylene chloride (50 ml) whilethe temperature of the mixture is kept at 0-5° C. After addition, themixture is stirred at room temperature for six hours. To the reactionmixture is added water, and the methylene chloride layer is collected,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue is recrystallized from isopropanol to give2-phthalimide-N,N-dipropylacetamide (12.5 g), m.p. 99-100° C.

(2) A mixture of the above product (12.5 g), hydrazine • monohydrate(4.3 g) and ethanol (150 ml) is refluxed for one hour. The reactionmixture is concentrated under reduced pressure, and chloroform is addedto the residue. The mixture is filtered, and to the filtrate is addedwater. The chloroform layer is collected, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure to give the desiredcompound (6.7 g) as an oily product.

REFERENCE EXAMPLES 46-58

The corresponding starting amine compounds are treated in the samemanner as in reference Example 45 to give the compounds as listed inTable 12.

                  TABLE 12                                                        ______________________________________                                        7 #STR30##                                                                    Ref. Ex.       R.sub.1                                                                              R.sub.2                                                 ______________________________________                                        46             Me     Me                                                      47             Et     Et                                                      48             i-Pr   i-Pr                                                    49             Bu     Bu                                                      50             Me     i-Bu                                                    51             Et     Pr                                                      52             H      Ph                                                      53             Me     Ph                                                      54             Et     Ph                                                      55             Bw     Ph                                                      56             Pr     Ph                                                      57             Me     Ph-4-Cl                                                 58             Me     Ph-4-OMe                                                ______________________________________                                    

REFERENCE EXAMPLE 59

Preparation of 2-amino-N-(4-fluorophenyl)-N-methylacetamide:

(1) The same procedure as Reference Example 45-(1) are repeated exceptthat 4-fluoroaniline (15 g) is used instead of dipropylamine. Theproduct thus obtained is purified by silica gel column chromatography(eluent; chloroform), and recrystallized from ethanol to giveN-(4-fluorophenyl)-2-phthalimidacetamide (19 g), m.p. 212-214° C.

(2) The above product (18 g) is added to a mixture of sodium hydride(about 60% oily, 3 g) and dimethylformamide (100 ml) at 0-5° C., and themixture is stirred at 0° C. for one hour. To the mixture is addeddropwise methyl iodide (10 g) at the same temperature. After addition,the mixture is stirred at room temperature for 8 hours. To the reactionmixture are added water and chloroform, and the chloroform layer iscollected, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue is purified by silica gel columnchromatography (eluent; chloroform), and recrystallized from ethanol togive N-(4-fluorophenyl)-N-methyl-2-phthalimidacetamide (15 g), m.p.182-183° C.

(3) The above product (14 g) is treated in the same manner as inReference Example 45-(2) to give the desired compound (9.0 g) as an oilyproduct.

REFERENCE EXAMPLE 60

Preparation of N-allyl-2-amino-N-phenylacetamide:

The same procedures as Reference Example 59 are repeated except thataniline and allyl bromide are used instead of 4-fluoroaniline inReference Example 59-(1) and methyl iodide in Reference Example 59-(2),respectively, to give the desired compound as an oily product.

REFERENCE EXAMPLE 61

Preparation of 2-amino-N-cyclopropylmethyl-N-phenylacetamide:

The same procedures as Reference Example 59 are repeated except thataniline and cyclopropylmethyl bromide are used instead of4-fluoroaniline in Reference Example 59-(1) and methyl iodide inReference Example 59-(2), respectively, to give the desired compound asan oily product.

REFERENCE EXAMPLES 62-66

The corresponding starting compounds are treated in the same manner asin Reference Example 59 to give the following compounds.

(Reference Example 62)

2-Amino-N-(4-bromophenyl)-N-methylacetamide

(Reference Example 63)

2-Amino-N-(2-chlorophenyl)-N-methylacetamide

(Reference Example 64)

2-Amino-N-(3-chlorophenyl)-N-methylacetamide

(Reference Example 65)

2-Amino-N-(4-chlorophenyl)-N-ethylacetamide

(Reference Example 66)

2-Amino-N-(4-chlorophenyl)-N-propylacetamide

REFERENCE EXAMPLES 67-69

The corresponding starting amine compounds are treated in the samemanner as in Reference Example 45 to give the following compounds.

(Reference Example 67)

1-Aminoacetyl-3,5-dimethylpiperidine

(Reference Example 68)

4-Aminoacetyl-2,6-dimethylmorpholine

(Reference Example 69)

1-Aminoacetyl-cis-3,5-dimethylpiperazine

REFERENCE EXAMPLE 70

Preparation of N-(4-chlorophenyl)-N-methyl-2-methylaminoacetamide:

(1) To a mixture of N-(tert-butoxycarbonyl)-N-methylglycine (10 g),4-chloroaniline (8.8 g),benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(BOP reagent, 25.7 g) and methylene chloride (150 ml) is added dropwisetriethylamine (5.9 g) while the temperature of the mixture is kept at0-5° C. After addition, the mixture is stirred at room temperature for 8hours, and thereto is added water. The methylene chloride layer iscollected, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue is purified by silica gel columnchromatography (eluent; chloroform), and recrystallized from diethylether to give2-[N'-(tert-butoxycarbonyl)-N'-methylamino]-N-(4-chlorophenyl)acetamide,m.p. 126-128° C.

(2) The above product (12 g) is added to a mixture of sodium hydride(about 60% oily, 3.2 g) and dimethylformamide (100 ml) at 0-5° C., andthe mixture is stirred at 0° C. for one hour, and then thereto is addedmethyl iodide (17 g) at the same temperature. After addition, themixture is stirred at room temperature for 8 hours, and thereto areadded water and chloroform. The chloroform layer is collected, driedover anhydrous sodium sulfate, and concentrated under reduced pressure.The residue is purified by silica gel column chromatography (eluent;chloroform) to give2-[N'-(tert-butoxycarbonyl)-N'-methylamino]-N-(4-chlorophenyl)-N-methylacetamide(11.4 g) as an oily product.

(3) To a mixture of the above product (8.4 g) and methylene chloride(100 ml) is added dropwise trifluoroacetic acid (20 ml) at 0-5° C. Afteraddition, the mixture is stirred at room temperature for three hours.The reaction mixture is concentrated under reduced pressure, and to theresidue is added water. The mixture is made weak basic with 1N aqueoussodium hydroxide solution while the mixture is stirred underice-cooling, and then thereto is added chloroform. The chloroform layeris collected, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure to give the desired compound (4.7 g) as an oilyproduct.

REFERENCE EXAMPLES 71-73

The corresponding starting tert-butoxycarbonylated amino acids aretreated in the same manner as in Reference Example 70 to give thefollowing compounds as an oily product.

(Reference Example 71)

N-(4-Chlorophenyl)-N-methyl-2-pyrrolidinecarboxyamide

(Reference Example 72)

N-(4-Chlorophenyl)-N-methyl-2-piperidinecarboxyamide

(Reference Example 73)

N-(4-Chlorophenyl)-2,3-dihydro-N-methyl-1H-indole-2-carboxyamide

REFERENCE EXAMPLES 74-80

The corresponding starting tert-butoxycarbonylated amino acids aretreated in the same manner as in Reference Example 70-(1), -(3) to givethe following compounds as an oily product.

(Reference Example 74)

2-Amino-3-benzyloxy-N,N-dipropylpropanamide

(Reference Example 75)

2-Methylamino-N,N-dipropylacetamide

(Reference Example 76)

2-Ethylamino-N,N-dipropylacetamide

(Reference Example 77)

2-Methylamino-N-methyl-N-phenylacetamide

(Reference Example 78)

2-Ethylamino-N-methyl-N-phenylacetamide

(Reference Example 79)

N,N-Dipropyl-2-pyrrolidinecarboxamide

(Reference Example 80)

2,3-Dihydro-N,N-dipropyl-1H-indolecarboxamide

REFERENCE EXAMPLE 81

Preparation of 2-hydroxy-N,N-dipropylacetamide:

(1) To a mixture of dipropylamine (5.0 g), triethylamine (5.5 g) andmethylene chloride (70 ml) is added dropwise a solution of ethyloxalylchloride (7.4 g) and methylene chloride (30 ml) with stirring while thetemperature of the mixture is kept at -20° C. After addition, themixture is stirred at 0° C. for four hours. To the reaction mixture isadded water, and the methylene chloride layer is collected, dried overanhydrous sodium sulfate, and concentrated under reduced pressure togive ethyl 2-oxo-2-(N,N-dipropylamino)acetate (9.5 g) as an oilyproduct.

(2) A mixture of the above product, sodium borohydride, lithium chlorideand anhydrous tetrahydrofuran is stirred at room temperature for 30minutes, and thereto is added dropwise anhydrous ethanol while thetemperature of the mixture is kept at 0-5° C. After addition, themixture is stirred at room temperature for 12 hours. The reactionmixture is cooled to 0° C., an the pH value thereof is adjusted to pH 5with 1N hydrochloric acid, and concentrated under reduced pressure. Tothe residue are added a saturated brine and chloroform, and thechloroform layer is collected, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure to give the desired compound (7.7 g)as an oily product.

REFERENCE EXAMPLE 82

Preparation of N,N-dibutyl-2-hydroxyacetamide:

The same procedures as Reference Example 81 are repeated except thatdibutylamine is used instead of dipropylamine to give the desiredcompound as an oily product.

REFERENCE EXAMPLE 83

Preparation of 2-bromo-N,N-dipropylacetamide:

To a mixture of dipropylamine (10.1 g), triethylamine (10.1 g) andanhydrous diethyl ether (80 ml) is added dropwise a solution ofbromoacetyl chloride (15.8 g) in anhydrous diethyl ether (40 ml) whilethe temperature of the mixture is kept at -40° C. After addition, thetemperature is gradually raised, and the mixture is stirred at roomtemperature for one hour. The reaction mixture is filtered, and thefiltrate is concentrated under reduced pressure, and purified bydistillation under reduced pressure to give the desired compound (14 g),b.p. 100-103° C./1 mmHg.

REFERENCE EXAMPLES 84-87

The corresponding starting compounds are treated in the same manner asin Reference Example 83 to give the following compounds.

(Reference Example 84)

2-Bromo-N,N-dipropylpropanamide; b.p. 85-87° C./I1 mmHg

(Reference Example 85)

2-Bromo-N-(4-chlorophenyl)-N-methylacetamide; m.p. 52-53° C.

(recrystallized from isopropanol)

(Reference Example 86)

2-Bromo-N-methyl-N-phenylpropanamide; b.p. 135-145° C./1 mmHg

(Reference Example 87)

2-Bromo-N-ethyl-N-phenylpropanamide; oily product

REFERENCE EXAMPLE 88

Preparation of 2-(5,6-dimethyl-2-phenyl-4-pyrimidinyloxy)acetic acid:

(1) To a mixture of sodium hydride (about 60% oily, 1.0 g) anddimethylformamide (80 ml) is added5,6-dimethyl-2-phenyl-4(3H)-pyrimidinone (5.0 g) while the temperatureof the mixture is kept at 0-5° C., and the mixture is stirred at 0° C.for 30 minutes. To the mixture is added dropwise ethyl bromoacetate (4.2g) at the same temperature. After addition, the mixture is stirred at80° C. for three hours, and thereto are added ice-water and chloroform.The chloroform layer is collected by filtration, washed with water,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue is purified by silica gel column chromatography(eluent; chloroform), and recrystallized from isopropanol to give ethyl2-(5,6-dimethyl-2-phenyl-4-pyrimidinyloxy)acetate (6.2 g), m.p. 90-91°C.

(2) A mixture of the above product (6.0 g), 1N aqueous sodium hydroxidesolution (100 ml) and ethanol (50 ml) is stirred at room temperature for8 hours. The reaction mixture is concentrated under reduced pressure,and the residue is dissolved in ice-water. The pH value of the mixtureis adjusted to pH 1 with conc. hydrochloric acid, and the precipitatesare collected by filtration, washed with water, and recrystallized fromethanol to give the desired compound (3.5 g), m.p. 175-177° C.

REFERENCE EXAMPLES 89-90

The corresponding starting compounds are treated in the same manner asin Reference Example 88, and the products thus obtained arerecrystallized from ethanol to give the following compounds.

(Reference Example 89)

2-(5,6,7,8-Tetrahydro-2-phenyl-4-quinazolinyloxy)acetic acid; m.p.155-157° C.

(Reference Example 90)

2-[2-(4-Chlorophenyl) -5,6,7,8-tetrahydro-4-quinazolinyloxy) aceticacid; m.p. 195-197° C.

REFERENCE EXAMPLES 91-92

The corresponding starting t-butoxycarbonylated amino acids are treatedin the same manner as in Reference Example 70 to give the followingcompounds as an oily product.

(Reference Example 91)

2-Methylamino-N-phenyl-N-propylacetamide

(Reference Example 92)

N-Allyl-2-methylamino-N-phenylacetamide

REFERENCE EXAMPLES 93-94

The corresponding starting t-butoxycarbonylated amino acids are treatedin the same manner as in Reference Example 70-(1) and -(3) to give thefollowing compounds as an oily product.

(Reference Example 93)

N,N-Diethyl-2-methylaminoacetamide

(Reference Example 94)

N-Ethyl-2-methylamino-N-phenylacetamide

EXAMPLE 1

Preparation of2-(5,6-dimethyl-2-phenyl-4-pyrimidinylamino)-N,N-dipropylacetamide:

A mixture of 4-chloro-5,6-dimethyl-2-phenylpyrimidine (1.0 g),2-amino-N,N-dipropylacetamide (0.87 g) and triethylamine (0.55 g) isrefluxed with stirring at 150° C. for three hours. To the reactionmixture are added water and chloroform, and the chloroform layer iscollected, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue is purified by silica gel columnchromatography (eluent; chloroform), and recrystallized from a mixtureof diethyl ether and n-hexane to give the desired compound (1.3 g), m.p.79-80° C.

EXAMPLES 2-63

The corresponding starting compounds are treated in the same manner asin Example 1 to give the compounds as listed in Table 13.

                                      TABLE 13                                    __________________________________________________________________________    8 #STR31##                                                                                                     Solv. for                                    Ex.                                                                              R.sub.1  R.sub.2                                                                             R.sub.7                                                                           Q    M.p. (°C.)                                                                   recrystal.                                   __________________________________________________________________________    2  Pr       Pr    4-Cl     74-75 E-HX                                         3  Pr       Pr    3-Cl     101-103                                                                             IP                                           4  Pr       Pr    4-F      70-71 E-HX                                         5  Pr       Pr    4-OMe    83-85 IP                                           6  Pr       Pr    4-CF.sub.3                                                                             83-85 HX-EA                                        7  Pr       Pr    4-NO.sub.2                                                                             135-137                                                                             IP                                           8  Me       Me    H        174-175                                                                             IP                                           9  Et       Et    H        113-114                                                                             E-HX                                         10 Et       Et    4-Cl     152-153                                                                             IP                                           11 Et       Et    4-F      139-140                                                                             IP                                           12 Et       Et    4-OMe    130-132                                                                             IP                                           13 i-Pr     i-Pr  H        171-172                                                                             IP                                           14 Bu       Bu    H        46-47 HX                                           15 Bu       Bu    4-Cl     52-53 HX                                           16 Bu       Bu    4-F      45-46 HX                                           17 Et       Pr    H        69-71 E-HX                                         18 Et       Pr    4-Cl     103-104                                                                             HX                                           19 Et       Pr    4-F      85-86 HX                                           20 Et       Pr    4-OMe    89-90 HX                                           21 Me       i-Bu  H        100-102                                                                             E-HX                                         22 Me       Ph    H        145-146                                                                             IP                                           23 Me       Ph    4-Cl     150-152                                                                             IP                                           24 Me       Ph    3-Cl     149-151                                                                             IP                                           25 Me       Ph    4-F      146-148                                                                             IP                                           26 Me       Ph    4-OMe    173-174                                                                             IP                                           27 Me       Ph    4-CF.sub.3                                                                             192-194                                                                             IP                                           28 Me       Ph    4-NO.sub.2                                                                             199-201                                                                             AC                                           29 Me       Ph-4-Cl                                                                             H        165-166                                                                             IP                                           30 Me       Ph-2-Cl                                                                             H        137-138                                                                             IP                                           31 Me       Ph-3-Cl                                                                             H        129-130                                                                             IP                                           32 Me       Ph-4-Cl                                                                             4-Cl     170-171                                                                             IP                                           33 Me       Ph-4-Cl                                                                             4-F      174-175                                                                             IP                                           34 Me       Ph-4-Cl                                                                             4-OMe    157-158                                                                             IP                                           35 Me       Ph-4-F                                                                              H   1/4 H.sub.2 O                                                                      140-142                                                                             A                                            36 Me       Ph-4-F                                                                              4-Cl     163-164                                                                             A                                            37 Me       Ph-4-Br                                                                             H        183-184                                                                             A                                            38 Me       Ph-4-Br                                                                             4-Cl     176-177                                                                             IP                                           39 Me       Ph-4-Br                                                                             4-F      184-185                                                                             IP                                           40 Me       Ph-4-Br                                                                             4-OMe    168-169                                                                             IP                                           41 Me       Ph-4-OMe                                                                            H        166-167                                                                             A                                            42 Me       Ph-4-OMe                                                                            4-Cl     173-174                                                                             A                                            43 Me       Ph-4-OMe                                                                            4-F      172-173                                                                             IP                                           44 Et       Ph    H        138-139                                                                             E                                            45 Et       Ph    4-Cl     142-143                                                                             IP                                           46 Et       Ph    3-Cl     135-137                                                                             IP                                           47 Et       Ph    4-F      132-133                                                                             IP                                           48 Et       Ph    4-OMe    133-134                                                                             IP                                           49 Et       Ph    4-CF.sub.3                                                                             166-167                                                                             IP                                           50 Et       Ph    4-NO.sub.2                                                                             180-182                                                                             AC                                           51 Et       Ph-4-Cl                                                                             H        194-196                                                                             A                                            52 Pr       Ph    H        148-149                                                                             IP                                           53 Pr       Ph    4-Cl     174-175                                                                             A                                            54 Pr       Ph    4-F      164-165                                                                             IP                                           55 Pr       Ph    4-OMe    125-126                                                                             IP                                           56 Pr       Ph-4-Cl                                                                             H        167-169                                                                             A                                            57 Bu       Ph    H        134-135                                            58 --CH.sub.2 CH═CH.sub.2                                                             Ph    H        125-126                                                                             IP                                           59 --CH.sub.2 CH═CH.sub.2                                                             Ph    4-Cl     151-152                                                                             A                                            60 --CH.sub.2 CH═CH.sub.2                                                             Ph    4-OMe    118-119                                                                             IP                                           61                                                                               9 #STR32##                                                                             Ph    H        105-106                                                                             E-HX                                         62                                                                               9 #STR33##                                                                             Ph    4-Cl     157-158                                                                             A                                            63 H        Ph    H        155-156                                                                             E                                            __________________________________________________________________________

EXAMPLES 64-68

The corresponding starting compounds are treated in the same manner asin Example 1 to give the following compounds.

(Example 64)

N-Cyclohexyl-N-methyl-2-(5,6-dimethyl-2-phenyl-4-pyrimidinylamino)-acetamide;m.p. 112-114° C. (recrystallized from n-hexane)

(Example 65)

3,5-Dimethyl-1-(5,6-dimethyl-2-phenyl-4-pyrimidinylamino)acetylpiperidine;m.p. 97-98° C. (recrystallized from n-hexane)

(Example 66)

(a)2,6-Dimethyl-4-(5,6-dimethyl-2-phenyl-4-pyrimidinylamino)acetylmorpholine;m.p. 151-152° C. (recrystallized from isopropanol)

(b)cis-2,6-Dimethyl-4-(5,6-dimethyl-2-phenyl-4-pyrimidinylamino)acetylmorpholine;

The compound obtained in Example 29a is purified by silica gel flashcolumn chromatography (eluent; n-hexane:ethyl acetate=3:1), and the lesspolar fractions are combined, concentrated under reduced pressure, andrecrystallized from isopropanol to give the desired compound, m.p.162-163° C.

(c)trans-2,6-Dimethyl-4-(5,6-dimethyl-2-phenyl-4-pyrimidinylamino)acetylmorpholine;

The compound obtained in Example 29a is purified by silica gel flashcolumn chromatography (eluent; n-hexane:ethyl acetate=3:1), and the morepolar fractions are combined, concentrated under reduced pressure, andrecrystallized from a mixture of diethyl ether and n-hexane to give thedesired compound, m.p. 112-113° C.

(Example 67)

cis-3,5-Dimethyl-1-(5,6-dimethyl-2-phenyl-5-pyrimidinylamino)acetylpiperazine;m.p. 134-137° C. (recrystallized from a mixture of diethyl ether andn-hexane)

(Example 68)

4-[2-(4-Chlorophenyl)-5,6-dimethyl-4-pyrimidinylamino]acetyl-2,6-dimethylmorpholine;m.p. 212-214° C. (recrystallized from isopropanol)

EXAMPLE 69

Preparation of3-hydroxy-2-(5,6-dimethyl-2-phenyl-4-pyrimidinylamino)-N,N-dipropylpropanamide:

(1) A mixture of 4-chloro-5,6-dimethyl-2-phenylpyrimidine (1.8 g),2-amino-3-benzyloxy-N,N-dipropylpropanamide (4.6 g), which is preparedfrom N-(tert-butoxycarbonyl)-O-benzylserine, and triethylamine (1.7 g)is stirred at 150° C. for 5 hours. The reaction mixture is treated inthe same manner as in Example 1 to give3-benzyloxy-2-(5,6-dimethyl-2-phenyl-4-pyrimidinylamino)-N,N-dipropylpropanamide(3.5 g) as an oily product.

(2) A mixture of the above product (3.4 g), acetic acid (50 ml), water(10 ml), ethanol (10 ml) and 10% palladium-carbon (0.5 g) is stirred at60° C. for five hours under hydrogen atmosphere, and the reactionmixture is filtered. The filtrate is concentrated under reducedpressure, and the residue is recrystallized from a mixture of diethylether and n-hexane to give the desired compound (2.5 g), m.p. 132-133°C.

EXAMPLE 70

Preparation of2-[methyl-(5,6-dimethyl-2-phenyl-4-pyrimidinyl)amino]-N,N-dipropylacetamide:

The same procedures as Example 1 are repeated except that2-methylamino-N,N-dipropylacetamide is used instead of2-amino-N,N-dipropylacetamide, and to the product thus obtained is addedhydrogen chloride isopropanol solution. The precipitated crystals arecollected by filtration, and washed with diethyl ether to give ahydrochloride 1/10 hydrate of the desired compound, m.p. 162-165° C.

EXAMPLES 71-78

The corresponding starting compounds are treated in the same manner asin Example 1 to give the compounds as listed in Table 14.

                  TABLE 14                                                        ______________________________________                                        0 #STR34##                                                                                                             Solv. for                            Ex.    R.sub.1                                                                              R.sub.2  R.sub.4                                                                            R.sub.7                                                                             M.p. (°C.)                                                                    recrystal.                           ______________________________________                                        71     Pr     Pr       Et   Cl    85-86  HX                                   72     Pr     Pr       Et   OMe   111-112                                                                              HX                                   73     Me     Ph       Me   H     117-119                                                                              IP                                   74     Me     Ph       Me   F     140-141                                                                              IP                                   75     Me     Ph       Me   OMe   151-152                                                                              IP                                   76     Me     Ph-4-Cl  Me   H     114-115                                                                              IP                                   77     Me     Ph       Et   H     107-108                                                                              HX                                   78     Me     Ph       Et   Cl    100-101                                                                              HX                                   ______________________________________                                    

EXAMPLE 79

Preparation ofN-(4-chlorophenyl)-N-methyl-1-(5,6-dimethyl-2-phenyl-4-pyrimidinyl)-2-pyrrolidinecarboxamide:

The same procedures as Example 1 are repeated except thatN-(4-chlorophenyl)-N-methyl-2-pyrrolidinecarboxamide is used instead of2-amino-N,N-dipropylacetamide, and to the product thus obtained is addedhydrogen chloride diethyl ether solution. The precipitated crystals arecollected by filtration, and washed with diethyl ether to give ahydrochloride of the desired compound, m.p. 119-121° C.

EXAMPLE 80

Preparation ofN-(4-chlorophenyl)-N-methyl-1-(5,6-dimethyl-2-phenyl-4-pyrimidinyl)-2-piperidinecarboxamide:

The same procedures as Example 1 are repeated except thatN-(4-chlorophenyl)-N-methyl-2-piperidinecarboxamide is used instead of2-amino-N,N-dipropylacetamide. The product thus obtained isrecrystallized from a mixture of diethyl ether and n-hexane to give a1/10 hydrochloride of the desired compound, m.p. 149-151° C.

EXAMPLE 81

Preparation of2,3-dihydro-1-(5,6-dimethyl-2-phenyl-4-pyrimidinyl)-N,N-dipropyl-1H-indole-2-carboxamide:

The same procedures as Example 1 are repeated except that2,3-dihydro-N,N-dipropyl-1H-indole-2-carboxamide is used instead of2-amino-N,N-dipropylacetamide. The product thus obtained isrecrystallized from n-hexane to give a 1/4 hydrate of the desiredcompound, m.p. 167-168° C.

EXAMPLE 82

Preparation ofN-(4-chlorophenyl)-2,3-dihydro-N-methyl-1-(5,6-dimethyl-2-phenyl-4-pyrimidinyl)-1H-indole-2-carboxamide:

The same procedures as Example 1 are repeated except thatN-(4-chlorophenyl)-2,3-dihydro-N-methyl-1H-indole-2-carboxamide is usedinstead of 2-amino-N,N-dipropylacetamide. The product thus obtained isrecrystallized from methanol to give a 1/10 hydrochloride.1/4 hydrate ofthe desired compound, m.p. 236-238° C.

EXAMPLE 83

Preparation of2-(5-ethyl-6-methyl-2-phenyl-4-pyrimidinylamino)-N,N-dipropylacetamide:

The same procedures as Example 1 are repeated except that4-chloro-5-ethyl-6-methyl-2-phenylpyrimidine is used instead of4-chloro-5,6-dimethyl-2-phenylpyrimidine. The product thus obtained isrecrystallized from a mixture of diethyl ether and n-hexane to give thedesired compound, m.p. 83-84° C.

EXAMPLE 84

Preparation ofN-(4-chlorophenyl)-2-(5-ethyl-6-methyl-2-phenyl-4-pyrimidinylamino)-N-methylacetamide:

The same procedures as Example 1 are repeated except that4-chloro-5-ethyl-6-methyl-2-phenylpyrimidine and2-amino-N-(4-chlorophenyl)-N-methylacetamide are used instead of4-chloro-5,6-dimethyl-2-phenylpyrimidine and2-amino-N,N-dipropylacetamide, respectively. The product thus obtainedis recrystallized from isopropanol to give the desired compound, m.p.142-143° C.

EXAMPLE 85

Preparation of2-(6-ethyl-5-methyl-2-phenyl-4-pyrimidinylamino)-N,N-dipropylacetamide:

The same procedures as Example 1 are repeated except that4-chloro-6-ethyl-5-methyl-2-phenylpyrimidine is used instead of4-chloro-5,6-dimethyl-2-phenylpyrimidine. The product thus obtained isrecrystallized from a mixture of diethyl ether and n-hexane to give thedesired compound, m.p. 83-84° C.

EXAMPLE 86

Preparation of2-(6-isopropyl-5-methyl-2-phenyl-4-pyrimidinylamino)-N,N-dipropylacetamide

The same procedures as Example 1 are repeated except that4-chloro-6-isopropyl-5-methyl-2-phenylpyrimidine is used instead of4-chloro-5,6-dimethyl-2-phenylpyrimidine. The product thus obtained isrecrystallized from a mixture of diethyl ether and n-hexane to give thedesired compound, m.p. 98-99° C.

EXAMPLE 87

Preparation of2-(6-methyl-2-phenyl-4-pyrimidinylamino)-N,N-dipropylacetamide:

The same procedures as Example 1 are repeated except that4-chloro-6-methyl-2-phenylpyrimidine is used instead of4-chloro-5,6-dimethyl-2-phenylpyrimidine. The product thus obtained isrecrystallized from diethyl ether to give the desired compound, m.p.107-108° C.

EXAMPLE 88

Preparation of2-(6-methyl-2-phenyl-4-pyrimidinylamino)-N-methyl-N-phenylacetamide:

The same procedures as Example 1 are repeated except that4-chloro-6-methyl-2-phenylpyrimidine and2-amino-N-methyl-N-phenylacetamide are used instead of4-chloro-5,6-dimethyl-2-phenylpyrimidine and2-amino-N,N-dipropylacetamide, respectively. The product thus obtainedis recrystallized from isopropanol to give the desired compound, m.p.134-136° C.

EXAMPLE 89

Preparation of2-(5-chloro-6-methyl-2-phenyl-4-pyrimidinylamino)-N-methyl-N-phenylacetamide:

A mixture of2-(6-methyl-2-phenyl-4-pyrimidinylamino)-N-methyl-N-phenylacetamide (1.0g) obtained in Example 88, N-chlorosuccinimide (0.44 g) and acetic acid(15 ml) is heated with stirring at 90° C. for three hours, and thereaction mixture is concentrated under reduced pressure. To the residueis added ice-water (30 ml) with stirring, and the precipitates arecollected by filtration, washed with water, and recrystallized fromisopropanol to give the desired compound (1.1 g), m.p. 154-155° C.

EXAMPLE 90

Preparation of2-(5-bromo-6-methyl-2-phenyl-4-pyrimidinylamino)-N-methyl-N-phenylacetamide:

The same procedures as Example 89 are repeated except thatN-bromosuccinimide is used instead of N-chlorosuccinimide. The productthus obtained is recrystallized from isopropanol to give the desiredcompound, m.p. 160-162° C.

EXAMPLE 91

Preparation of2-(2-phenyl-6-trifluoromethyl-4-pyrimidinylamino)-N,N-dipropyl-acetamide:

The same procedures as Example 1 are repeated except that4-chloro-6-trifluoromethyl-2-phenylpyrimidine is used instead of4-chloro-5,6-dimethyl-2-phenylpyrimidine. The product thus obtained isrecrystallized from isopropanol to give the desired compound, m.p.128-130° C.

EXAMPLE 92

Preparation of2-(5-chloro-2-phenyl-6-trifluoromethyl-4-pyrimidinylamino)-N,N-dipropylacetamide:

The same procedures as Example 89 are repeated except that2-(2-phenyl-6-trifluoromethyl-4-pyrimidinylamino)-N-methyl-N-phenylacetamideis used instead of2-(6-methyl-2-phenyl-4-pyrimidinylamino)-N-methyl-N-phenylacetamide. Theproduct thus obtained is recrystallized from isopropanol to give thedesired compound, m.p. 115-117° C.

EXAMPLES 93-99

The corresponding starting compounds are treated in the same manner asin Example 1 to give the compounds as listed in Table 15.

                  TABLE 15                                                        ______________________________________                                        1 #STR35##                                                                                                         M.p.   Solv. for                         Ex.  R.sub.1                                                                              R.sub.2 R.sub.5                                                                            R.sub.7                                                                            Q      (°C.)                                                                         recrystal.                        ______________________________________                                        93   Pr     Pr      H    H           102-103                                                                              E-HX                              94   Pr     Pr      H    Cl          146-148                                                                              IP                                95   Me     Ph      H    Cl   1/10 HCl                                                                             180-181                                                                              A                                 96   Me     Ph-4-Cl H    H    1/4 H.sub.2 O                                                                        157-158                                                                              IP                                97   Pr     Pr      Me   H           139-140                                                                              IP                                98   Pr     Pr      Me   Cl          129-130                                                                              IP                                99   Me     Ph      Me   H           146-147                                                                              IP                                ______________________________________                                    

EXAMPLE 100

Preparation of3,5-dimethyl-1-(2,6-diphenyl-4-pyrimidinylamino)acetylpiperidine:

The same procedures as Example 1 are repeated except that4-chloro-2,6-diphenylpyrimidine and 1-aminoacetyl-3,5-dimethylpiperidineare used instead of 4chloro-5,6-dimethyl-2-phenylpyrimidine and2-amino-N,N-dipropylacetamide, respectively. The product thus obtainedis recrystallized from isopropanol to give the desired compound, m.p.134-135° C.

EXAMPLE 101

Preparation of 2-(2-phenyl-4-pyrimidinylamino)-N,N-dipropylacetamide:

The same procedures as Example 1 are repeated except that4-chloro-2-phenylpyrimidine, which is prepared according to the methoddisclosed in Rec. Trav. Chim. Pays-Bas, 86, 15 (1967), is used insteadof 4-chloro-5,6-dimethyl-2-phenylpyrimidine. The product thus obtainedis recrystallized from diethyl ether to give the desired compound, m.p.74-75° C.

EXAMPLE 102

Preparation of2-(5,6,7,8-tetrahydro-2-phenyl-4-quinazolinylamino)-N,N-dipropylacetamide:

A mixture of 4-chloro-5,6,7,8-tetrahydro-2-phenylquinazoline (1.0 g),2-amino-N,N-dipropylacetamide (0.78 g) and triethylamine (0.5 g) isrefluxed with stirring at 150° C. for three hours. To the reactionmixture are added water and chloroform, and the chloroform layer isseparated, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue is purified by silica gel columnchromatography (eluent; chloroform), and recrystallized from a mixtureof diethyl ether and n-hexane to give the desired compound (1.3 g), m.p.87-88° C.

EXAMPLES 103-112

The corresponding starting compounds are treated in the same manner asin Example 102 to give the compounds as listed in Table 16.

                  TABLE 16                                                        ______________________________________                                        2 #STR36##                                                                                                           M.p. Solv. for                         Ex.  R.sub.1                                                                              R.sub.2 R.sub.4                                                                            R.sub.7                                                                           Q         (°C.)                                                                       recrystal.                        ______________________________________                                        103  Pr     Pr      H    F             88-  HX                                                                       89                                     104  Pr     Pr      H    Cl            98-  E-HX                                                                     99                                     105  Bu     Bu      H    H             71-  HX                                                                       72                                     106  Bu     Bu      H    F             65-  HX                                                                       66                                     107  Bu     Bu      H    Cl            83-  HX                                                                       84                                     108  Me     Ph-4-Cl H    H             225- M                                                                        227                                    109  Me     Ph-4-Cl H    Cl            177- IP                                                                       178                                    110  Pr     Pr      Me   H   HCl, 3/4 H.sub.2 O                                                                      154- IP                                                                       156                                    111  Me     Ph-4-Cl Me   H   1/10 HCl  176- IP                                                                       177                                    112  Me     Ph-4-Cl Me   F             139- IP                                                                       140                                    ______________________________________                                    

EXAMPLES 113-117

The corresponding starting compounds are treated in the same manner asin Example 102 to give the compounds as listed in Table 17.

                  TABLE 17                                                        ______________________________________                                        3 #STR37##                                                                                                      Solv. for                                   Ex.       A      R.sub.7   M.p. (°C.)                                                                    recrystal.                                  ______________________________________                                        113       O      H         164-165                                                                              IP                                          114       O      F         212-214                                                                              A                                           115       O      Cl        225-227                                                                              A                                           116       NH     H         178-179                                                                              IP                                          117       NH     F         195-197                                                                              IP                                          ______________________________________                                    

EXAMPLE 118

Preparation of3-hydroxy-2-(5,6,7,8-tetrahydro-2-phenyl-4-quinazolinylamino)-N,N-dipropylpropanamide:

(1) The same procedures as Example 102 are repeated except that2-amino-3-benzyloxy-N,N-dipropylpropanamide (4.1 g) is used instead of2-amino-N,N-dipropylacetamide to give3-benzyloxy-2-(5,6,7,8-tetrahydro-2-phenyl-4-quinazolinylamino)-N,N-dipropylpropanamide(3.4 g) as an oily product.

(2) A mixture of the above product (3.0 g), acetic acid (100 ml) and 10%palladium-carbon (1.0 g) is stirred at 60° C. for six hours underhydrogen atmosphere, and the reaction mixture is filtered. The filtrateis concentrated under reduced pressure and recrystallized from diethylether to give the desired compound (2.0 g), m.p. 119-120° C.

EXAMPLES 119-120

Instead of 2-amino-N,N-dipropylacetamide, the corresponding startingcompounds are treated in the same manner as in Example 102 to give thefollowing compounds.

(Example 119)

1-(5,6,7,8-Tetrahydro-2-phenyl-4-quinazolinyl)-N,N-dipropyl-2-pyrrolidinecarboxamide;m.p. 123-124° C. (recrystallized from diethyl ether)

(Example 120)

N-(4-Chlorophenyl)-1-(5,6,7,8-tetrahydro-2-phenyl-4-quinazolinyl)-N-methyl-2-pyrrolidinecarboxamide1/4 hydrate; m.p. 80-82° C. (recrystallized from n-hexane)

EXAMPLE 121

Preparation of2-(5-nitro-2-phenyl-4-pyrimidinylamino)-N,N-dipropylacetamide:

A mixture of 4-chloro-5-nitro-2-phenylpyrimidine (6.0 g),2-amino-N,N-dipropylacetamide (6.0 g), triethylamine (5.2 g) andisopropanol (70 ml) is refluxed for six hours. The reaction mixture isconcentrated under reduced pressure, and to the residue are addedchloroform and water. The chloroform layer is collected, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue is purified by silica gel column chromatography (eluent;chloroform), and recrystallized from ethanol to give the desiredcompound (8.8 g), m.p. 142-143° C.

EXAMPLE 122

Preparation of2-(5-amino-2-phenyl-4-pyrimidinylamino)-N,N-dipropylacetamide;

A mixture of2-(5-nitro-2-phenyl-4-pyrimidinylamino)-N,N-dipropylacetamide (1.9 g)obtained in Example 121, ethanol (60 ml) and 10% palladiumcarbon (0.2 g)is stirred at room temperature for three hours under hydrogenatmosphere, and the reaction mixture is filtered. The filtrate isconcentrated under reduced pressure, and recrystallized from diethylether to give the desired compound (1.5 g), m.p. 120-122° C.

EXAMPLE 123

Preparation ofN-methyl-2-(5-nitro-2-phenyl-4-pyrimidinylamino)-N-phenylacetamide:

The same procedures as Example 121 are repeated except that2-amino-N-methyl-N-phenylacetamide (7.3 g) is used instead of2-amino-N,N-dipropylacetamide. The product thus obtained isrecrystallized from ethanol to give the desired compound (10.1 g), m.p.194-196° C.

EXAMPLE 124

Preparation of2-(5-amino-2-phenyl-4-pyrimidinylamino)-N-methyl-N-phenylacetamide:

2-(5-Nitro-2-phenyl-4-pyrimidinylamino)-N-methyl-N-phenylacetamide (5.5g) obtained in Example 123 is treated in the same manner as in Example122, and the product thus obtained is recrystallized from ethanol togive a 1/4 hydrate of the desired compound (4.8 g), m.p. 183-184° C.

EXAMPLE 125

Preparation of2-(5-acetylamino-2-phenyl-4-pyrimidinylamino)-N-methyl-N-phenylacetamide:

A mixture of2-(5-amino-2-phenyl-4-pyrimidinylamino)-N-methyl-N-phenylacetamide (3.6g) obtained in Example 124, acetic anhydride (10 ml) and pyridine (7 ml)is stirred at room temperature for four hours. To the reaction mixtureis added chloroform, and the mixture is washed with 1N hydrochloricacid, then washed with a saturated aqueous sodium hydrogen carbonatesolution. The chloroform layer is collected, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue ispurified by silica gel column chromatography (eluent; chloroform), andrecrystallized from ethanol to give the desired compound (4.0 g), m.p.200-201° C.

EXAMPLE 126

Preparation of2-(5-ethoxycarbonyl-2-phenyl-4-pyrimidinylamino)-N,N-dipropylacetamide:

The same procedures as Example 1 are repeated except that4-chloro-5-ethoxycarbonyl-2-phenylpyrimidine (6.0 g) is used instead of4-chloro-5,6-dimethyl-2-phenylpyrimidine. The product thus obtained isrecrystallized from n-hexane to give the desired compound, m.p. 45-46°C.

EXAMPLE 127

Preparation of2-(5-hydroxymethyl-2-phenyl-4-pyrimidinylamino)-N,N-dipropylacetamide:

To a mixture of2-(5-ethoxycarbonyl-2-phenyl-4-pyrimidinylamino)-N,N-dipropylacetamide(3.0 g) obtained in Example 126, sodium borohydride (0.6 g), lithiumchloride (0.7 g) and tetrahydrofuran (20 ml) is added dropwise anhydrousethanol (30 ml) at 0 to 5° C. The reaction mixture is stirred at roomtemperature for five hours, and the pH value thereof is adjusted to pH 5with 1N hydrochloric acid, and concentrated under reduced pressure. Tothe residue are added a brine and chloroform, and the chloroform layeris collected, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue is purified by silica gel columnchromatography (eluent; chloroform), and recrystallized from isopropanolto give the desired compound (2.0 g), m.p. 167-168° C.

EXAMPLE 128

Preparation of2-[2-(4-fluorophenyl)-5,6,7,8-tetrahydro-4-quinazolinyloxy]-N,N-dipropylacetamide:

To a mixture of 2-hydroxy-N,N-dipropylacetamide (1.8 g) anddimethylformamide (20 ml) is added sodium hydride (about 60% oily, 0.5g) at 0 to 5° C., and the mixture is stirred at 0° C. for one hour. Tothe reaction mixture is added4-chloro-2-(4-fluorophenyl)-5,6,7,8-tetrahydroquinazoline (2.0 g) at thesame temperature, and the mixture is stirred at room temperature forfour hours. To the mixture are added chloroform and ice-water, and thechloroform layer is collected, washed with water, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue ispurified by silica gel column chromatography (eluent; chloroform), andrecrystallized from a mixture of diethyl ether and n-hexane to give thedesired compound (2.2 g), m.p. 95-96° C.

EXAMPLES 129-135

The corresponding starting compounds are treated in the same manner asin Example 128 to give the compounds as listed in Table 18.

                  TABLE 18                                                        ______________________________________                                                                                Solv. for                             Ex.    R.sub.1                                                                              R.sub.2 R.sub.7                                                                            R.sub.8                                                                             M.p. (°C.)                                                                    recrystal.                            ______________________________________                                        129    Pr     Pr      2-Cl H     75-76  HX                                    130    Pr     Pr      3-Cl H     100-101                                                                              HX                                    131    Pr     Pr      4-Cl H     119-120                                                                              IP                                    132    Pr     Pr      2-F  4-F   93-94  HX                                    133    Bu     Bu      H    H     84-85  HX                                    134    Bu     Bu      4-F  H     90-91  HX                                    135    Bu     Bu      4-Cl H     105-106                                                                              IP                                    ______________________________________                                    

EXAMPLE 136

Preparation of2-(5,6-dimethyl-2-phenyl-4-pyrimidinyloxy)-N,N-dipropylacetamide:

To a mixture of 5,6-dimethyl-2-phenyl-4-(3H)-pyrimidinone (1.5 g) anddimethylformamide (20 ml) is added sodium hydride (about 60% oily, 0.3g) at 0-5° C., the mixture is stirred at 0° C. for one hour. To themixture is added 2-dipropylacetamide (1.67 g) at the same temperature,and the mixture is stirred at room temperature for two hours. To thereaction mixture are added chloroform and ice-water, and the chloroformlayer is collected, washed with water, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue ispurified by silica gel column chromatography (eluent; chloroform), andrecrystallized from n-hexane to give the desired compound (2.2 g), m.p.88-89° C.

EXAMPLE 137-163

The corresponding starting compounds are treated in the same manner asin Example 136 to give the compounds as listed in Table 19.

                                      TABLE 19                                    __________________________________________________________________________    1 #STR38##                                                                                                    Solve. for                                    Ex.                                                                              R.sub.5                                                                          R.sub.6                                                                          R.sub.1                                                                          R.sub.2                                                                            R.sub.7                                                                            Q    M.p. (°C.)                                                                  recrystal.                                    __________________________________________________________________________    137                                                                              Me Me Pr Pr   4-Cl      128-130                                                                            E-HX                                          138                                                                              Me Me Pr Pr   4-F       131-133                                                                            A                                             139                                                                              Me Me Pr Pr   4-OMe     87-88                                                                              HX                                            140                                                                              Me Me Pr Pr   3-Cl      82-84                                                                              E-HX                                          141                                                                              Me Me Pr Pr   4-CF.sub.3                                                                              109-111                                                                            HX                                            142                                                                              Me Me Pr Pr   4-NO.sub.2                                                                              157-159                                                                            M                                             143                                                                              Me Me Me Ph   H         138-139                                                                            IP                                            144                                                                              Me Me Me Ph   4-Cl      159-161                                                                            A                                             145                                                                              Me Me Me Ph   3-Cl      170-173                                                                            IP                                            146                                                                              Me Me Me Ph   4-OMe     157-159                                                                            IP                                            147                                                                              Me Me Me Ph   4-CF.sub.3                                                                              159-161                                                                            IP                                            148                                                                              Me Me Me Ph   4-NO.sub.2                                                                              179-181                                                                            AC                                            149                                                                              Me Me Me Ph-4-Cl                                                                            H         168-170                                                                            IP                                            150                                                                              Me Me Me Ph-4-Cl                                                                            4-OMe     142-143                                                                            A                                             151                                                                              Me Me Et Ph   H         130-132                                                                            IP                                            152                                                                              Me Me Et Ph   4-Cl      170-171                                                                            A                                             153                                                                              Me Me Et Ph   3-Cl      151-153                                                                            IP                                            154                                                                              Me Me Et Ph   4-F       156-158                                                                            IP                                            155                                                                              Me Me Et Ph   4-CF.sub.3                                                                              148-150                                                                            IP                                            156                                                                              Et Me Me Ph-4-Cl                                                                            H         100-101                                                                            E-HX                                          157                                                                              Me Et Pr Pr   H         62-63                                                                              HX                                            158                                                                              H  Ph Pr Pr   H         82-83                                                                              E                                             159                                                                              Me Ph Pr Pr   H         78-79                                                                              HX                                            160                                                                              H  CF.sub.3                                                                         Pr Pr   H         109-110                                                                            IP                                            161                                                                              --(CH.sub.2).sub.4 --                                                               Pr Pr   H         92-93                                                                              E-HX                                          162                                                                              --(CH.sub.2).sub.4 --                                                               Me Ph-4-Cl                                                                            H         140-141                                                                            IP                                            163                                                                              --(CH.sub.2).sub.4 --                                                               Me Ph-4-Cl                                                                            4-Cl 1/4 H.sub.2 O                                                                      200-202                                                                            A                                             __________________________________________________________________________

EXAMPLE 164

Preparation ofN-ethyl-2-[5,6-dimethyl-2-(4-nitrophenyl)-4-pyrimidinyloxy]-N-phenylacetamide:

The same procedures as Example 136 are repeated except that5,6-dimetyl-2-(4-nitrophenyl)-4-(3H)-pyrimidinone and2-bromo-N-ethyl-N-phenylacetamide are used instead of5,6-dimethyl-2-phenyl-4-(3H)-pyrimidinone and2-bromo-N,N-dipropylacetamide, respectively. The product thus obtainedis recrystallized from acetonitrile to give the desired compound, m.p.89-190° C.

EXAMPLE 165

Preparation of2-[2-(4-aminophenyl)-5,6-dimethyl-4-pyrimidinyloxy]-N-ethyl-N-phenylacetamide:

A mixture of2-[5,6-dimethyl-2-(4-nitrophenyl)-4-pyrimidinyloxy]-N-ethyl-N-phenylacetamide(2.3 g) obtained in Example 164, 5% palladiumcarbon (0.4 g), ethanol (30ml) and chloroform (10 ml) is stirred at room temperature for threehours under hydrogen atmosphere, and the reaction mixture is filtered.The filtrate is concentrated under reduced pressure, and recrystallizedfrom acetonitrile to give a 1/10 hydrate of the desired compound (2.1g), m.p. 183-185° C.

EXAMPLE 166

Preparation of2-(6-methyl-2-phenyl-4-pyrimidinyloxy)-N,N-dipropylacetamide:

The same procedures as Example 136 are repeated except that6-methyl-2-phenyl-4-(3H)-pyrimidinone is used instead of5,6-dimethyl-2-phenyl-4-(3H)-pyrimidinone. The product thus obtained isrecrystallized from n-hexane to give the desired compound, m.p. 68-69°C.

EXAMPLE 167

Preparation of2-(5-chloro-6-methyl-2-phenyl-4-pyrimidinyloxy)-N,N-dipropylacetamide:

2-(6-Methyl-2-phenyl-4-pyrimidinyloxy)-N,N-dipropylacetamide obtained inExample 166 is treated in the same manner as in Example 89, and theproduct is recrystallized from isopropanol to give the desired compound,m.p. 90-91° C.

EXAMPLE 168

Preparation of2-(5-bromo-6-methyl-2-phenyl-4-pyrimidinyloxy)-N,N-dipropylacetamide:

2-(6-Methyl-2-phenyl-4-pyrimidinyloxy)-N,N-dipropylacetamide obtained inExample 166 is treated in the same manner as in Example 90, and theproduct is recrystallized from isopropanol to give the desired compound,m.p. 107-108° C.

EXAMPLE 169

Preparation of2-(5,6,7,8-tetrahydro-2-phenyl-4-quinazolinyloxy)-N,N-dipropylpropanamide:

The same procedures as Example 136 are repeated except that5,6,7,8-tetrahydro-2-phenyl-4-(3H)-quinazolinone and2-bromo-N,N-dipropylpropanamide are used instead of5,6-dimethyl-2-phenyl-4-(3H)-pyrimidinone and2-bromo-N,N-dipropylacetamide, respectively. The product thus obtainedis recrystallized from n-hexane to give the desired compound, m.p.73-74° C.

EXAMPLE 170

Preparation of3,5-dimethyl-1-(5,6-dimethyl-2-phenyl-4-pyrimidinyloxy)acetylpiperidine:

To a mixture of 2-(5,6-dimethyl-2-phenyl-4-pyrimidinyloxy)acetic acid(1.2 g), 3,5-dimethylpiperidine (0.7 g),benzotriazol-1-yloxy-tris(dimethylamino)phosphonium •hexafluorophosphate (BOP reagent; 2.26 g) and dimethylformamide (20 ml)is added triethylamine (0.52 g) at 0-5° C., and the mixture is stirredat room temperature for six hours. To the reaction mixture are addedchloroform and ice-water, and the chloroform layer is collected, washedwith water, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue is purified by silica gel columnchromatography (eluent; chloroform), and recrystallized from n-hexane togive the desired compound (1.4 g), m.p. 100-101° C.

EXAMPLES 171-173

Instead of 3,5-dimethylpiperidine, the corresponding starting compoundsare treated in the same manner as in Example 170 to give the followingcompounds.

(Example 171)

2,6-Dimethyl-4-(5,6-dimethyl-2-phenyl-4-pyrimidinyloxy)acetylmorpholine;m.p. 123-124° C. (recrystallized from isopropanol)

(Example 172)

3,5-Dimethyl-1-(5,6-dimethyl-2-phenyl-4-pyrimidinyloxy)acetylpiperazine• 1/4 hydrate; m.p. 107-1 10° C. (recrystallized from a mixture ofdiethyleter and n-hexane)

(Example 173)

2,3-Dihydro-1-(5,6-dimethyl-2-phenyl-4-pyrimidinyloxy)acetyl-1H-indole;m.p. 210-212° C. (recrystallized from acetonitrile)

EXAMPLES 174-188

The corresponding starting compounds are treated in the same manner asin Example 170 to give the compounds as listed in Table 20.

                  TABLE 20                                                        ______________________________________                                        2 #STR39##                                                                                                               Solv. for                          Ex.  R.sub.5                                                                              R.sub.6                                                                              R.sub.1                                                                            R.sub.2                                                                              R.sub.7                                                                            M.p. (°C.)                                                                    recrystal.                         ______________________________________                                        174  Me     Me     Me   Me     H    128-129                                                                              IP                                 175  Me     Me     Et   Et     H    88-90  E-HX                               176  Me     Me     Et   Et     Cl   148-149                                                                              IP                                 177  Me     Me     Bu   Bu     H     99-100                                                                              E-HX                               178  Me     Me     Pr   Ph     H    151-152                                                                              IP                                 179  --(CH.sub.2).sub.4 --                                                                   Et     Et     H    100-101                                                                              E-HX                                 180  --(CH.sub.2).sub.4 --                                                                   Me     Ph     H    135-137                                                                              IP                                   181  --(CH.sub.2).sub.4 --                                                                   Me     Ph     Cl   148-150                                                                              IP                                   182  --(CH.sub.2).sub.4 --                                                                   Pr     Ph     H    158-160                                                                              IP                                   183  --(CH.sub.2).sub.4 --                                                                   H      Ph-4-F H    178-179                                                                              M                                    184  --(CH.sub.2).sub.4 --                                                                   Me     Ph-4-F H    164-165                                                                              IP                                   185  --(CH.sub.2).sub.4 --                                                                   H      Ph-4-Cl                                                                              H    179-180                                                                              A                                    186  --(CH.sub.2).sub.4 --                                                                   Me     Ph-2-Cl                                                                              H    165-166                                                                              A                                    187  --(CH.sub.2).sub.4 --                                                                   Me     Ph-3-Cl                                                                              H    180-182                                                                              A                                    188  --(CH.sub.2).sub.4 --                                                                   Me     CH.sub.2 Ph                                                                          H    91-92  E                                    ______________________________________                                    

EXAMPLE 189

Preparation of2-(5,6-dimethyl-2-phenyl-4-pyrimidinyloxy)-N-phenylacetamide:

The same procedures as Example 170 are repeated except that aniline isused instead of 3,5-dimethylpiperidine. The product thus obtained isrecrystallized from isopropanol to give the desired compound, m.p.212-213° C.

EXAMPLE 190

Preparation ofN-cyclopropylmethyl-2-(5,6-dimethyl-2-phenyl-4-pyrimidinyloxy)-N-phenylacetamide:

To a mixture of2-(5,6-dimethyl-2-phenyl-4-pyrimidinyloxy)-N-phenylacetamide (1.5 g)obtained in Example 189 and dimethylformamide (30 ml) is added sodiumhydride (about 60% oily, 0.2 g) at 0-5° C., and the mixture is stirredat 0° C. for one hour. To the mixture is added cyclopropylmethyl bromide(0.67 g) at the same temperature, and the mixture is stirred at roomtemperature for two hours. To the reaction solution are added chloroformand ice-water, and the chloroform layer is collected, washed with water,and dried over anhydrous sodium sulfate. The chloroform layer isconcentrated under reduced pressure, and the residue is purified bysilica gel column chromatography (eluent; chloroform), andrecrystallized from isopropanol to give the desired compound (1.56 g),m.p. 119-121° C.

EXAMPLE 191

Preparation ofN-allyl-2-(5,6-dimethyl-2-phenyl-4-pyrimidinyloxy)-N-phenylacetamide:

The same procedures as Example 190 are repeated except that allylbromide is used instead of propylmethyl bromide. The product thusobtained is recrystallized from isopropanol to give the desiredcompound, m.p. 129-131 ° C.

EXAMPLES 192-196

The corresponding starting compounds are treated in the same manner asin Example 170 to give the following compounds.

(Example 192)

1-(5,6,7,8-Tetrahydro-2-phenyl-4-quinazolinyloxy)acetyl-3,5-dimethylpiperidine;m.p. 134-135° C. (recrystallized from diethyl ether)

(Example 193)

4-(5,6,7,8-Tetrahydro-2-phenyl-4-quinazolinyloxy)acetyl-2,6-dimethylmorpholine;m.p. 161-163° C. (recrystallized from isopropanol)

(Example 194)

1-(5,6,7,8-Tetrahydro-2-phenyl-4-quinazolinyloxy)acetyl-cis-3,5-dimethylpiperazine1/4 hydrate; m.p. 150-151° C. (recrystallized from diethyl ether)

(Example 195)

4-[2-(4-Chlorophenyl)-5,6,7,8-tetrahydro-4-quinazolinyloxy]acetyl-2,6-dimethylmorpholine; m.p. 171-173° C. (recrystallized fromisopropanol)

(Example 196)

1-[2-(4-Chlorophenyl)-5,6,7,8-tetrahydro-4-quinazolinyloxy]acetyl-cis-3,5-dimethylpiperazine• 9/10 hydrochloride; m.p. 265-268° C. (recrystallized from ethanol)

EXAMPLE 197

Preparation ofcis-3,5-dimethyl-1-[(5,6-dimethyl-2-phenyl-4-pyrimidinyl)-2-pyrrolidinylcarbonyl]piperazine:

(1) The same procedures as Example 1 are repeated except that prolinebenzyl ester hydrochloride (4.0 g) is used instead of2-amino-N,N-dipropylacetamide. The product thus obtained isrecrystallized from isopropanol to give1-(5,6-dimethyl-2-phenyl-4-pyrimidinyl)-2-pyrrolidinecarboxylic acid(4.0 g), m.p. 90-92° C.

(2) A mixture of the above product (3.8 g), ethanol (100 ml) and 10%palladium-carbon (1.0 g) is stirred at room temperature for 8 hoursunder hydrogen atmosphere, and the mixture is filtered. The filtrate isconcentrated under reduced pressure, and recrystallized from isopropanolto give N-(5,6-dimethyl-2-phenyl-4-pyrimidinyl)proline (2.5 g), m.p.228-231 ° C.

(3) To a mixture of the above product (1.2 g),cis-3,5-dimethylpiperazine (0.6 g), BOP reagent (1.97 g) anddimethylformamide (30 ml) is added triethylamine (0.52 g) at 0-5° C.,and the mixture is stirred at room temperature for five hours. To thereaction mixture are added chloroform and ice-water, and the chloroformlayer is collected, washed with water, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue ispurified by silica gel column chromatography (eluent; chloroform), andrecrystallized from diethyl ether to give a 1/2 hydrate of the desiredcompound (1.4 g), m.p. 160-162° C.

EXAMPLES 198-204

The corresponding starting compounds are treated in the same manner asin Example 1 to give the compounds as listed in Table 21.

                  TABLE 21                                                        ______________________________________                                        3 #STR40##                                                                                                       M.p.   Solv. for                           Ex.   R.sub.1      R.sub.2                                                                              R.sub.4                                                                            R.sub.7                                                                           (°C.)                                                                         recrystal.                          ______________________________________                                        198   Et           Et     Me   Cl  131-132                                                                              IP                                  199   Pr           Pr     Me   Cl  84-86  HX                                   200* Me           Ph     Me   Cl  139-140                                                                              IP                                  201   Et           Ph     Me   Cl  102-103                                                                              HX                                  202   Pr           Ph     Me   Cl  103-104                                                                              HX                                  203   --CH.sub.2 CH═CH.sub.2                                                                 Ph     Me   Cl  107-108                                                                              HX                                  204   H            Ph     H    Cl  205-206                                                                              A                                   ______________________________________                                         *1/4 Hydrate                                                             

EXAMPLE 205

Preparation of1-[2-(4-chlorophenyl)-5,6-dimethyl-4-pyrimidinyl]-N-(4-chlorophenyl)-N-methyl-2-pyrrolidinecarboxamide:

The corresponding starting compounds are treated in the same manner asin Example 1, and the product thus obtained is recrystallized fromisopropanol to give the title compound, m.p. 131-133° C.

Preparation 1: Preparation of tablets:

    ______________________________________                                        2-[2-(4-Chlorophenyl)-5,6-dimethyl-4-pyrimidinyl-                                                        1     g                                            amino]-N-methyl-N-phenylacetamide                                             Lactose                    84    g                                            Corn starch                30    g                                            Crystalline cellulose      25    g                                            Hydroxypropyl cellulose    3     g                                            Light anhydrous silicic acid                                                                             0.7   g                                            Magnesium stearate         1.3   g                                            ______________________________________                                    

The above components are mixed and kneaded in a conventional manner, andthe mixture is granulated, and the resultants are further tabletted togive 1,000 tablets (each 145 mg).

Preparation 2: Preparation of tablets

    ______________________________________                                        2-[5,6-Dimethyl-2-(4-trifluoromethylphenyl)-                                                            25    g                                             4-pyrimidinylamino]-N,N-dipropylacetamide                                     Lactose                   70    g                                             Corn starch               20    g                                             Crystalline cellulose     25    g                                             Hydroxypropyl cellulose   3     g                                             Light anhydrous silicic acid                                                                            0.7   g                                             Magnesium stearate        1.3   g                                             ______________________________________                                    

The above components are mixed and kneaded in a conventional manner, andthe mixture is granulated, and the resultants are further tabletted togive 1,000 tablets (each 145 mg).

Preparation 3: Preparation of capsules

    ______________________________________                                        2-[2-(4-Chlorophenyl)-5,6-dimethyl-4-pyrimidinyl-                                                       2      g                                            amino]-N,N-dipropylacetamide                                                  Lactose                   165    g                                            Corn starch               25     g                                            Hydroxypropyl cellulose   3.5    g                                            Light anhydrous silicic acid                                                                            1.8    g                                            Magnesium stearate        2.7    g                                            ______________________________________                                    

The above components are mixed and kneaded in a conventional manner, andthe mixture is granulated, and each 200 mg of the resultant is packedinto a capsule to give 1,000 capsules.

Preparation 4: Preparation of powder

    ______________________________________                                        N-(4-Chlorophenyl)-N-methyl-2-(5,6-dimethyl-                                                            10     g                                            2-phenyl-4-pyrimidinylamino)acetamide                                         Lactose                   960    g                                            Hydroxypropyl cellulose   25     g                                            Light anhydrous silicic acid                                                                            5      g                                            ______________________________________                                    

The above components are mixed to give powder preparation.

Preparation 5: Preparation of injection preparation

    ______________________________________                                        2-[2-(4-Chlorophenyl)-5,6-dimethyl-4-pyrimidinyl-                                                        10     g                                           amino]-N-methyl-N-phenylacetamide                                             Ethanol                    200    g                                           HCO-60                     2      g                                           Citric acid                10     g                                           Sorbitol                   50     g                                           Sodium hydroxide           q.s.                                               Distilled water for injection                                                                            q.s                                                Totally                    2000   ml                                          ______________________________________                                    

2-[2-(4-Chlorophenyl)-5,6-dimethyl-4-pyrimidinylamino]-N-methyl-N-phenylacetamideis dissolved in a mixture of ethanol and HCO-60, and thereto is added asuitable amount of distilled water for injection, and further theretoare added citric acid and sorbitol. The pH value of the mixture isadjusted to pH 4.5 with sodium hydroxide, and the total amount of themixture is controlled with addition of distilled water for injection.The solution thus obtained is filtered on a membrane filter (0.22 μm),and the filtrate is put into ampules (capacity; 2 ml), and the ampulesare sterilized at 121° C. for 20 minutes.

INDUSTRIAL APPLICABILITY

As explained above, the present compounds of the formula (I) or apharmaceutically acceptable acid addition salt thereof show a selectiveand remarkable affinity for the peripheral-type BZω₃ -receptor as wellas show excellent pharmacological activities such as anxiolyticactivity, antiepileptic activity, etc. in animal tests, and hence, theyare useful in the prophylaxis or treatment of central nervous disorderssuch as anxiety-related diseases (neurosis, somatoform disorders, otheranxiety disorders), depression, epilepsy, etc., or circulatory organsdisorders such as angina pectoris, hypertension, etc. Besides, thepresent compounds of the formula (I) and a pharmaceutically acceptableacid addition salt thereof can be expected to be useful in theprophylaxis or treatment of immuno neurological disorders such asmultiple sclerosis, and immuno inflammatory diseases such as rheumatoidarthritis.

We claim:
 1. An acetamide derivative of the formula (I): ##STR41##wherein X is --O-- or --NR₄ --, R₁ is a hydrogen atom, a C₁ -C₅ alkylgroup, a C₃ -C₆ alkenyl group or a C₃ -C₈ cycloalkyl-C₁ -C₄ alkylgroup,R₂ is a C₁ -C₆ alkyl group, a C₃ -C₈ cycloalkyl group, a phenylgroup which may optionally be substituted by one or two groups selectedfrom a halogen atom, a C₁ -C₃ alkyl group, a C₁ -C₃ alkoxy group, atrifluoromethyl group, an amino group, a mono- or di-C₁ -C₃ alkylaminogroup, a cyano group and a nitro group, or a phenyl-C₁ -C₄ alkyl groupwherein the phenyl moiety may optionally be substituted by one or twogroups selected from a halogen atom, a C₁ -C₃ alkyl group, a C₁ -C₃alkoxy group, a trifluoromethyl group, an amino group, a mono- or di-C₁-C₃ alkylamino group, a cyano group and a nitro group, or R₁ and R₁ mayoptionally combine together with the nitrogen atom to which they areattached to form a group of the formula: ##STR42## wherein A is a singlebond, --CH₂ --, --O-- or --NH--, R_(a) and R_(b) are the same ordifferent and each a hydrogen atom or a C₁ -C₆ alkyl group, or when A isa single bond, and R_(a) and R_(b) are located at the 2-position and the3-position, respectively, the carbon atoms of the 2-position and the3-position and R_(a) and R_(b) may optionally combine to form a phenylring, R₃ is a hydrogen atom, a C₁ -C₆ alkyl group or a hydroxy-C₁ -C₄alkyl group, R₄ is a hydrogen atom or a C₁ -C₆ alkyl group, or R₃ and R₄may optionally combine together with the carbon atom and the nitrogenatom to which they are attached to form pyrrolidine, piperidine, or2,3-dihydro-1H-indole ring, R₅ is a hydrogen atom, a C₁ -C₆ alkyl group;a C₃ -C₆ alkenyl group; a hydroxy-C₁ -C₄ alkyl group; a C₁ -C₄ alkylgroup substituted by a benzyloxy group wherein the phenyl moiety mayoptionally be substituted by one or two groups selected from a halogenatom, a C₁ -C₃ alkyl group and a C₁ -C₃ alkoxy group; a C₁ -C₄ alkylgroup substituted by a C₂ -C₄ alkanoyloxy group or a benzoyloxy groupwhich may optionally be substituted by one or two groups selected from ahalogen atom, a C₁ -C₃ alkyl group and a C₁ -C₃ -alkoxy group; a C₁ -C₅alkoxy-C₁ -C₄ alkyl group; a trifluoromethyl group; a halogen atom; anamino group a mono or di-C₁ -C₄ alkylamino group; a C₂ -C₄ alkanoylaminogroup; a benzoylamino group which may optionally be substituted by oneor two groups selected from a halogen atom, a C₁ -C₃ alkyl group and aC₁ -C₃ alkoxy group; an amino-C₁ -C₄ alkyl group; a nitro group; acarbamoyl group; a mino- or di-C₁ -C₄ alkylcarbamoyl group a carboxylgroup; a carboxyl group being protected by a C₁ -C₄ alkyl group or abenzyl group which may optionally be substituted by one or two groupsselected from a halogen atom, a C₁ -C₃ alkyl group and a C₁ -C₃ alkoxygroup; a carboxy-C₁ -C₄ alkyl group; or a C₁ -C₄ alkyl group beingsubstituted by a carboxyl group which is protected by a C₁ -C₄ alkylgroup or a benzyl group which may optionally be substituted by one ortwo groups selected from a halogen atom, a C₁ -C₃ alkyl group and a C₁-C₃ alkoxy group; R₆ is a hydrogen atom, a C₁ -C₆ alkyl group, atrifluoro-methyl group or a phenyl group which may optionally besubstituted by one or two groups selected from a halogen atom, a C₁ -C₃alkyl group, a C₁ -C₃ alkoxy group, a trifluoro-methyl group, an aminogroup, a mono- or di-C₁ -C₃ alkylamino group, a cyano group and a nitrogroup, or R₅ and R₆ may optionally combine to form --(CH₂)_(n) --, R₇ isa hydrogen atom, a halogen atom, a C₁ -C₆ alkyl group, a C₁ -C₆ alkoxygroup, a trifluoromethyl group, a hydroxy group, an amino group, a mono-or di-C₁ -C₄ alkylamino group, a cyano group or a nitro group, R₈ is ahydrogen atom, a halogen atom, a C₁ -C₆ alkyl group or a C₁ -C₆ alkoxygroup, or a pharmaceutically acceptable acid addition salt thereof. 2.The compound according to claim 1, wherein R₅ is a hydrogen atom, a C₁-C₆ alkyl group, a hydroxy-C₁ -C₄ alkyl group, a halogen atom, an aminogroup, a C₂ -C₄ alkanoylamino group, a benzoylamino group which mayoptionally be substituted by one or two groups selected from a halogenatom, a C₁ -C₃ alkyl group and a C₁ -C₃ alkoxy group, a nitro group or acarboxyl group being protected by a C₁ -C₄ alkyl group or a benzyl groupwhich may optionally be substituted by one or two groups selected from ahalogen atom, a C₁ -C₃ alkyl group and a C₁ -C₃ alkoxy group.
 3. Thecompound according to claim 1, wherein R₁ and R₂ are the same ordifferent and each a C₁ -C₆ alkyl group, or R₁ is a C₁ -C₆ alkyl group,a C₃ -C₆ alkenyl group or a C₃ -C₈ cycloalkyl-C₁ -C₄ alkyl group, and R₂is a phenyl group which may optionally be substituted by one or twogroups selected from a halogen atom, a C₁ -C₃ alkyl group, a C₁ -C₃alkoxy group, a trifluoromethyl group, an amino group, a mono- or di-C₁-C₃ alkylamino group, a cyano group and a nitro group, or R₁ and R₂ mayoptionally combine together with the nitrogen atom to which they areattached to form a group of the formula: ##STR43## wherein A' is --CH₂-- or --O--, and R_(a) ' and R_(b) ' are the same or different and eacha C₁ -C₆ alkyl group, and R₅ is a hydrogen atom, a C₁ -C₆ alkyl group, ahydroxy-C₁ -C₄ alkyl group, a halogen atom, an amino group, a C₂ -C₄alkanoylamino group, a benzoylamino group which may optionally besubstituted by one or two groups selected from a halogen atom, a C₁ -C₃alkyl group and a C₁ -C₃ -alkoxy group, a nitro group or a carboxylgroup being protected by a C₁ -C₄ alkyl group or a benzyl group whichmay optionally be substituted by one or two groups selected from ahalogen atom, a C₁ -C₃ alkyl group and a C₁ -C₃ alkoxy group.
 4. Thecompound according to claim 1, wherein R₁ and R₂ are the same ordifferent and each a methyl group, an ethyl group, a propyl group, anisopropyl group or a butyl group, or R₁ is a methyl group, an ethylgroup, a propyl group, an isopropyl group, a butyl group, an allyl groupor a cyclopropylmethyl group, and R₂ is a phenyl group or a phenyl groupbeing substituted by a halogen atom or a methoxy group, R₃ is a hydrogenatom, R₅ is a hydrogen atom, a methyl group, an ethyl group or ahydroxymethyl group, R₆ is a methyl group or a phenyl group, or R₅ andR₆ may optionally combine to form --(CH₂)₄ --, R₇ is a hydrogen atom, ahalogen atom, a C₁ -C₃ alkoxy group, a trifluoromethyl group, an aminogroup or a nitro group, and R₈ is a hydrogen atom.
 5. The compoundaccording to claim 4, wherein X is --O-- or --NR₄ --, R₁ and R₂ are thesame or different and each an ethyl group, a propyl group or a butylgroup, or R₁ is a methyl group, an ethyl group, a propyl group, an allylgroup or a cyclopropylmethyl group, and R₂ is a phenyl group, ahalogenophenyl group or a methoxyphenyl group, R₃ is a hydrogen atom, R₄' is a hydrogen atom, a methyl group or an ethyl group, or R₃ and R₄ 'may optionally combine together with the carbon atom and the nitrogenatom to which they are attached to form a pyrrolidine ring or a2,3-dihydro-1H-indole ring, R₇ is a hydrogen atom, a halogen atom, amethoxy group, a trifluoromethyl group, an amino group or a nitro group,and R₈ is a hydrogen atom.
 6. An acetamide derivative of the formula(I'): ##STR44## wherein X' is --O-- or --NR₄ "--, R₁ ' and R₂ ' are bothan ethyl group or a propyl group, or R₁ ' is a methyl group, an ethylgroup, a propyl group, an allyl group or a cyclopropylmethyl group, R₂ 'is a phenyl group or a 4-halogenophenyl group, or a 4-methoxyphenylgroup, R₃ ' is a hydrogen atom, R₄ " is a hydrogen atom, a methyl group,or an ethyl group, R₇ ' is a hydrogen atom, a halogen atom, a methoxygroup, a trifluoromethyl group, an amino group or a nitro group, or apharmaceutically acceptable acid addition salt thereof.
 7. The compoundaccording to claim 6, wherein X' is --NH--.
 8. The compound according toclaim 6, wherein X' is --O--.
 9. An acetamide derivative of the formula(I"): ##STR45## wherein R₁ ' and R₂ ' are both an ethyl group or apropyl group, or R₁ ' is a methyl group, an ethyl group, a propyl group,an allyl group or a cyclopropylmethyl group, R₂ ' is a phenyl group or a4-halogenophenyl group or a 4-methoxyphenyl group, R₅ ' is a hydrogenatom, a methyl group or an ethyl group, R₇ ' is a hydrogen atom, ahalogen atom, a methoxy group, a trifluoromethyl group, an amino groupor a nitro group, or a pharmaceutically acceptable acid addition saltthereof.
 10. A compound which is selected from the followingcompounds:2-[2-(4-chlorophenyl)-5,6-dimethyl-4-pyrimidinylamino]-N,N-diethyl-acetamide;N-(4-chlorophenyl)-N-methyl-2-(5,6-dimethyl-2-phenyl-4-pyrimidinylamino)acetamide;2-[2-(4-chlorophenyl)-5,6-dimethyl-4-pyrimidinylamino]-N-(4-fluorophenyl)-N-methylacetamide;2-[2-(4-chlorophenyl)-5,6-dimethyl-4-pyrimidinylamino]-N-(4-methoxyphenyl)-N-methylacetamide;2-(5,6-dimethyl-2-phenyl-4-pyrimidinylamino)-N-phenyl-N-propylacetamide:and2-[2-(4-chlorophenyl)-5,6-dimethyl-4-pyrimidinylamino]-N-ethyl-N-phenylacetamide,or a pharmaceutically acceptable acid addition salt thereof.
 11. Acompound which is selected from the followingcompounds:2-(5,6-dimethyl-2-phenyl,-4-pyrimidinyloxy)-N,N-dipropylacetamide;2-(2,6-diphenyl-4-pyrimidinylamino)-N,N-dipropylacetamide;2-[5,6-dimethyl-2-(4-trifluoromethylphenyl)-4-pyrimidinylamino]-N,N-dipropylacetamide;N-ethyl-2-[5,6-dimethyl-2-(4-aminophenyl)-4-pyrimidinyloxy]-N-phenylacetamide;2-[2-(4-chlorophenyl)-5,6-dimethyl-4-pyrimidinyloxy]-N-methyl-N-phenylacetamide;and2-(5,6-dimethyl-2-phenyl-4-pyrimidinyloxy)-N-phenyl-N-propylacetamide,or a pharmaceutically acceptable acid addition salt thereof. 12.2-[2-(4-Chlorophenyl)-5,6-dimethyl-4-pyrimidinylamino]-N,N-dipropylacetamide,or a pharmaceutically acceptable acid addition salt thereof. 13.2-[2-(4-Chlorophenyl)-5,6-dimethyl-4-pyrimidinylamino]-N-methyl-N-phenylacetamide,or a pharmaceutically acceptable acid addition salt thereof.
 14. Aprocess for preparing an acetamide derivative of the formula (I):##STR46## wherein X is --O-- or --NR₄ --, R₁ is a hydrogen atom, a C₁-C₆ alkyl group, a C₃ -C₆ alkenyl group or a C₃ -C₈ cycloalkyl-C₁ -C₄alkyl group,R₂ is a C₁ -C₆ alkyl group, a C₃ -C₈ cycloalkyl group, aphenyl group which may optionally be substituted by one or two groupsselected from a halogen atom, a C₁ -C₃ alkyl group, a C₁ -C₃ alkoxygroup, a trifluoromethyl group, an amino group, a mono- or di-C₁ -C₃alkylamino group, a cyano group and a nitro group, or a phenyl-C₁ -C₄alkyl group wherein the phenyl moiety may optionally be substituted byone or two groups selected from a halogen atom, a C₁ -C₃ alkyl group, aC₁ -C₃ alkoxy group, a trifluoromethyl group, an amino group, a mono- ordi-C₁ -C₃ alkylamino group, a cyano group and a nitro group, or R₁ andR₂ may optionally combine together with the nitrogen atom to which theyare attached to form a group of the formula: ##STR47## wherein A is asingle bond, --CH₂ --, --O-- or --NH--, and R_(a) and R_(b) are the sameor different and each a hydrogen atom or a C₁ -C₆ alkyl group, or when Ais a single bond, and R_(a) and R_(b) are located at the 2-position andthe 3-position, respectively, the carbon atoms of the 2-position and the3-position and R_(a) and R_(b) may optionally combine to form a phenylring, R₃ is a hydrogen atom, a C₁ -C₆ alkyl group or a hydroxy-C₁ -C₄alkyl group, R₄ is a hydrogen atom or a C₁ -C₆ alkyl group, or R₃ and R₄may optionally combine together with the carbon atom and the nitrogenatom to which they are attached to form a pyrrolidine, a piperidine, ora 2,3-dihydro-1H-indole ring, R₅ is a hydrogen atom; a C₁ -C₆ alkylgroup; a C₃ -C₆ alkenyl group; a hydroxy-C₁ -C₄ alkyl group, a C₁ -C₄alkyl group substituted by a benzyloxy group wherein the phenyl moietymay optionally be substituted by one or two groups selected from ahalogen atom, a C₁ -C₃ alkyl group and a C₁ -C₃ alkoxy group; a C₁ -C₄alkyl group substituted by a C₂ -C₄ alkanoyloxy group or a benzoyloxygroup which may optionally be substituted by one or two groups selectedfrom a halogen atom, a C₁ -C₃ alkyl group and a C₁ -C₃ -alkoxy group; aC₁ -C₆ alkoxy-C₁ -C₄ alkyl group; a trifluoromethyl group, a halogenatom; an amino group; a mono- or di-C₁ -C₄ alkylamino group; a C₂ -C₄alkanoylamino group; a benzoylamino group which may optionally besubstituted by one or two groups selected from a halogen atom, a C₁ -C₃alkyl group and a C₁ -C₃ alkoxy group; an amino-C₁ -C₄ alkyl group; anitro group; a carbamoyl group; a mono- or di-C₁ -C₄ alkylcarbamoylgroup; a carboxyl group; a carboxyl group being protected by a C₁ -C₄alkyl group or a benzyl group which may optionally be substituted by oneor two groups selected from a halogen atom, a C₁ -C₃ alkyl group and aC₁ -C₃ alkoxy group; a carboxy-C₁ -C₄ alkyl group; or a C₁ -C₄ alkylgroup being substituted by a carboxyl group which is protected by a C₁-C₄ aklyl group or a benzyl group which may optionally be substituted byone or two groups selected from a halogen atom, a C₁ -C₃ alkyl group anda C₁ -C₃ alkoxy group; R₆ is a hydrogen atom, a C₁ -C₆ alkyl group, atrifluoro-methyl group or a phenyl group which may optionally besubstituted by one or two groups selected from a halogen atom, a C₁ -C₃alkyl group, a C₁ -C₃ alkoxy group a trifluoro-methyl group an aminogroup, a mono- or di-C₁ -C₃ alkylamino group, a cyano group and a nitrogroup, or R₅ and R₆ may optionally combine to form --(CH₂)_(n) --, R₇ isa hydrogen atom, a halogen atom, a C₁ -C₆ alkyl group, a C₁ -C₆ alkoxygroup, a trifluoromethyl group, a hydroxy group, an amino group, a mono-or di-C₁ -C₄ alkylamino group, a cyano group or a nitro group, R₈ is ahydrogen atom, a halogen atom, a C₁ -C₆ alkyl group or a C₁ -C₆ alkoxygroup, or a pharmaceutically acceptable acid addition salt thereof,which comprises the following processes (a), (b), (c), (d), or (e):(a):when the compound (I) is a compound of the formula (I) wherein X is--NR₄ -- reacting a compound of the formula (II): ##STR48## wherein Z isa leaving atom or a leaving group, R₅₁ is the same groups as definedabove for R₅ except that a hydroxy-C₁ -C₄ alkyl group, an amino group,an amino-C₁ -C₄ alkyl group, a carboxyl group and a carboxy-C₁ -C₄ alkylgroup are protected ones, and R₆, R₇ and R₈ are the same as definedabove, with a compound of the formula (III): ##STR49## wherein R₃₁ is ahydrogen atom, a C₁ -C₆ alkyl group or a hydroxy-C₁ -C₄ alkyl groupbeing protected by a benzyloxy group, a 4-chlorobenzyloxy group, a3-bromobenzyloxy group, a 4-fluoribenzyloxl group, a 4-methylbenzyloxygroup, or a 4-methoxy-benzyloxy group, and R₁, R₂ and R₄ are the same asdefined above, optionally followed by removing the protecting groupsfrom the product, or (b) when the compound (I) is a compound of theformula (I) wherein X is --O--, and R₃ is a hydrogen atom, reacting acompound of the formula (II): ##STR50## wherein Z₁ is a halogen atom,and R₅₁, R₆, R₇ and R₈ are the same as defined above, with a compound ofthe formula (V): ##STR51## wherein R₁ and R₂ are the same as definedabove in the presence of a base, and optionally followed by removing theprotecting groups from the product, or (c) when the compound (I) is acompound of the formula (I) wherein X is --O--, reacting a compound ofthe formula (IVa): ##STR52## wherein R₅₁, R₆, R₇ and R₈ are the same asdefined above, with a compound of the formula (VII): ##STR53## whereinZ₁, R₁, R₂ and R₃₁ are the same as defined above in the presence of abase, if necessary, followed by removing the protecting groups from theproduct, or (d) reacting a compound of the formula (VIII): ##STR54##wherein X, R₃₁, R₅₁, R₆, R₇ and R₈ are the same as defined above, or areactive derivative thereof, with a compound of the formula (IX):##STR55## wherein R₁ and R₂ are the same as defined above, optionallyfollowed by removing the protecting groups from the product, or (e) whenthe compound (I) is a compound of the formula (I) wherein R₁ is a C₁ -C₆alkyl group, a C₃ -C₆ alkenyl group or a C₃ -C₈ cycloalkyl-C_(1-C) ₄alkyl group, reacting a compound of the formula (XII): ##STR56## whereinX, R₂, R₃, R₅, R₆, R₇, and R₈ are the same as defined above, with acompound of the formula (XIII):

    R.sub.11 --Z.sub.1

wherein R₁₁ is a C₁ -C₆ alkyl group, a C₃ -C₆ alkenyl group or a C₃ -C₈cycloalkyl-C_(1-C) ₄ alkyl group, and Z₁ is the same as defined above ina solvent, optionally followed by removing any protecting groups fromthe product, and optionally converting the product thus obtained into apharmaceutically acceptable acid addition salt thereof.
 15. Apharmaceutical composition which contains as an active ingredient atherapeutically effective amount of the acetamide derivative as setforth in claim 1, or a pharmaceutically acceptable acid addition saltthereof, and a pharmaceutically acceptable carrier or diluent.
 16. Apharmaceutical composition which contains as an active ingredient atherapeutically effective amount of the acetamide derivative as setforth in claim 6, or a pharmaceutically acceptable acid addition saltthereof, and a pharmaceutically acceptable carrier or diluent.
 17. Amethod for treatment of neurosis, somatoform disorders and anxietydisorders, which comprises administering a therapeutically effectiveamount of the acetamide derivative as set forth in claim 1, or apharmaceutically acceptable acid addition salt thereof, to a patientwith neurosis, somatoform disorders and anxiety disorders.
 18. A methodfor treatment of immuno inflammatory diseases, which comprisesadministering a therapeutically effective amount of the acetamidederivative as set forth in claim 1, or a pharmaceutically acceptableacid addition salt thereof, to a patient with immuno inflammatorydiseases.
 19. A method for treatment of immuno inflammatory diseases,which comprises administering a therapeutically effective amount of oneof the followingcompounds:2-(5,6-dimethyl-2-phenyl-4-pyrimidinyloxy)-N,N-dipropyl-acetamide;2-(2,6-diphenyl-4-pyrimidinylamino)-N,N-dipropylacetamide;2-[5,6-dimethyl-2-(4-trifluoromethylphenyl)-4-pyrimidinyl-amino]-N,N-dipropylacetamide;2-[2-(4-aminophenyl)-5,6-dimethyl-4-pyrimidinyloxy]-N-ethyl-N-phenylacetamide;2-[2-(4-chlorophenyl)-5,6-dimethyl-4-pyrimidinyloxy]-N-methyl-N-phenylacetamide;and2-(5,6-dimethyl-2-phenyl-4-pyrimidinyloxy)-N-phenyl-N-propyl-acetamide,or a pharmaceutically acceptable acid addition salt thereof, to apatient of immuno inflammatory disease.